By STEVEN ZECOLA
This research tracks the decades-long journey to harness alpha-synuclein as a remedy for Parkinson’s illness. Steven Zecola an activist who tracks Parkinson’s analysis and was on THCB final month discussing it, affords three key modifications wanted to beat the underlying challenges.
A Fast Begin for Alpha-Synuclein R&D
Within the mid-1990’s, Parkinson’s affected person advocacy teams had develop into impatient by the absence of any main therapeutic advances within the 25 years since L-dopa had been authorized for Parkinson’s illness (PD).
The Director of Nationwide Institute of Neurological Issues and Stroke (NINDS) arrange a workshop in August 1995 that featured scientists with experience in human genetics who may open novel avenues for PD analysis.
One such scientist, Robert Nussbaum, made the next remarks on the workshop:
“…discovering genes accountable for familial Parkinson’s must be useful for understanding all types of the illness. Strategies now out there ought to enable researchers to seek out the genes accountable for familial Parkinson’s illness in a comparatively quick time.”
Two years later in 1997, Spillantini et al. confirmed that alpha-synuclein (A-syn) was a serious contributor of irregular clusters of proteins within the mind, not solely in sufferers with synuclein mutations however, extra importantly, in sufferers with sporadic Parkinson’s illness as effectively.
As Nussbaum had predicted, progress had occurred quickly. President Clinton in his 1998 State of the Union tackle, stated:
“Take into consideration this, your entire retailer of human data now doubles each 5 years. Within the 1980’s, scientists recognized the gene inflicting cystic fibrosis. It took 9 years. Final 12 months scientists situated the gene that causes Parkinson’s illness in solely 9 days.”
The NIH is Requested to Take a Management Function
Shortly after President Clinton’s name to motion, a Senate Committee requested the Nationwide Institutes of Well being (NIH) to develop a coordinated effort to benefit from promising alternatives in PD analysis.
In response, the NIH and the Nationwide Institute of Neurological Illness and Stroke (NINDS) held a serious planning assembly that included all parts of the PD group. The group’s suggestions shaped the idea of a five-year PD Analysis Agenda.
The Analysis Agenda was codified in a complete 42-page report that lined all facets of analysis from higher understanding the illness, to creating new analysis capabilities, to creating new therapies, and to enhancing the analysis course of.
Noting the “exceptional paradigm shift in Parkinson’s illness analysis” from the invention of the consequences of alpha-synuclein, the report acknowledged that:
“New insights into the position of synucleins within the pathobiology of Parkinson’s illness would speed up discovery of simpler therapies and supply recent analysis alternatives to advance our understanding of Parkinson’s illness”.
NIH invested almost $1 billion from FY 2000 to FY 2004 to implement the PD Analysis Agenda. A-syn analysis could be funded out of the funds allotted to the classes of Genetics and Epidemiology, with each classes focused to obtain about 15% of the general spending.
Total, there have been 19 broad classes with spending authorizations, together with $32.7 million allotted to Program Administration and Route.
When the PD Analysis Agenda reached the tip of its 5-year span, NINDS sponsored a second PD Summit which was held in June 2005. It introduced collectively an industry-wide consortium to evaluate the progress over the earlier 5 years and to develop future instructions for PD analysis.
The individuals generated greater than fifty particular suggestions. NIH thought-about these plans and the unmet objectives from earlier efforts and developed a 3-year Plan.
A significant focus of that Plan was to determine and intervene with the causes of PD.
As reiterated within the 2006 Plan:
“…Understanding the position of alpha-synuclein could allow methods to selectively block the dangerous results related to this protein as a novel strategy to remedy of PD”.
NINDS famous that:
“Whereas PD isn’t a uncommon or orphan illness, different extra prevalent illnesses equivalent to stroke, weight problems and diabetes supply significantly bigger “markets” for drug therapies than does PD. Thus, pharmaceutical firms have primarily centered on medicinal chemistry and alterations of current PD or different neurological medicine (e.g., dopamine agonists) moderately than investing in new medicine.”
In essence, NINDS acknowledged the monetary conundrum of drug growth for A-syn and different PD therapies, however seemed to academia to resolve the issue by its grant program.
Missing success from the efforts of the 2006 Plan, NINDS organized one other convention in January 2014 known as: Parkinson’s Illness 2014: Advancing Analysis, Bettering Lives. The aim of this initiative was to determine vital challenges and to spotlight the very best priorities for advancing analysis.
Thirty-one suggestions have been supplied. The abstract of the convention included the High 3 priorities for medical analysis, translational analysis, and fundamental analysis. Below fundamental analysis, priorities 1 and a pair of associated to alpha-synuclein.
On condition that the work specified for A-syn analysis was nonetheless at an early stage of fundamental analysis in 2014, it’s clear that a big hole existed between the earlier NINDS priorities for A-syn and what was delivered.
Personal Pursuits Lastly Transfer Ahead with Alpha-Synuclein
Recognizing the persevering with lack of progress and the necessity for funding, the Michael J. Fox Basis introduced a $10-million “Ken Griffin Alpha-synuclein Imaging Competitors” in 2019 to spur growth of a essential and elusive imaging analysis instrument for Parkinson’s illness.
In March 2023, MJFF introduced that the three preliminary Alpha-synuclein imaging competitors groups — AC Immune, Mass Basic Brigham and Merck— made large developments within the growth of various alpha-synuclein tracer strategies.
MJFF awarded Merck a further $1.5 million to proceed the work and produce its instrument to life. The primary-in-human medical trial of its alpha-synuclein PET tracer started in 2023.
Moreover, after greater than twenty years of fundamental analysis, 5 personal analysis firms filed purposes with the FDA and have initiated early-stage PD trials.
- Neuropore Therapies and UCB are collaborating on an oral small molecule, which goals to forestall the formation of alpha-synuclein clusters.
- Prothena Biosciences, at the side of Roche, is testing a humanized anti-alpha-synuclein antibody.
- Biogen is investigating one other monoclonal antibody in opposition to alpha-synuclein.
- AFFiRiS, an Austrian biotech firm, is testing an alpha-synuclein vaccine. AC Immune has lately introduced the acquisition of all of AFFiRiS’ property and underlying mental property associated to its vaccine candidates concentrating on a-syn.
- Vaxxinity makes use of an immunotherapy candidate codenamed UB–312 to focus on poisonous types of aggregated α-synuclein within the mind to combat Parkinson’s. Its Chairman lately stated that: “Our findings counsel UB-312 may rework Parkinson’s care, providing hope for improved outcomes with a disease-modifying remedy”.
As with all R&D initiatives, there are lots of remaining challenges within the growth of A-syn therapies earlier than reaching the market. However, assuming that a minimum of one of many 5 on-going trials shall be profitable, we will count on a remedy using A-syn shall be authorized by the FDA inside the subsequent 5-8 years. The web impact is that the general growth window between A-syn’s discovery in 1997 and its software to sufferers could be roughly 35 years – assuming that the analysis goes comparatively easily from right here.
Given its efficiency so far, the view from NIH concerning PD analysis is:
“… Our failures in bringing therapies to the purpose line are because of remaining massive gaps in data of the underlying biology that causes and drives the illness. As we fill in these gaps, the possibilities of success will improve. Among the gaps we find out about, others we solely discover out about when the science opens one other door”.
Why Has This Analysis Taken So Lengthy?
With the good thing about hindsight, we will level to 2 areas that accounted for the best obstacles to progress – focus and assets.
In studying the PD analysis plans and studies from 2000, 2006 and 2014, it seems that NINDS threw every thing it knew about PD into the hopper. There have been a whole bunch of suggestions, initiatives and so-called priorities. However a key issue of success in analysis is having a workforce of motivated scientists with the required expertise, data and pondering potential to resolve a finely-honed query.
There merely are usually not sufficient nice minds to trace down all the “to do’s” within the three NINDS PD analysis plans. Additionally, communications and networking are necessary parts of scientific development, but the aptitude to community with the widespread participation within the small grants program was missing.
The implication of utilizing the time period “focus” is that it comes with the project of accountability and accountability if the precedence doesn’t get executed. There seems to be little outdoors oversight of the effectivity and effectiveness of the analysis {dollars} that have been utilized on A-syn or different PD analysis initiatives. If something, NIH appears content material with the output.
Lastly, NIH/NINDS knew there was a funding drawback in crossing the Valley of Loss of life from fundamental analysis to medical trials, however these organizations fell again to their consolation zone, specifically small grants to academicians. This technique didn’t produce the required outcomes.
A Higher Strategy
In 1998 and thereafter, alpha-synuclein wanted a swat workforce of top-flight researchers together with a dedication for added funds because the challenge progressed out of fundamental analysis and thru the requisite medical trials.
To handle the shortcomings so far, the Division of Well being and Human Companies (HHS) ought to step in and 1) slender the PD analysis precedence checklist to the highest candidates, 2) require the institution of a sturdy communications community for sharing info and three) chill out the FDA laws for PD to assist degree the fund-raising taking part in subject.
Particularly, HHS/NIH/NINDS should acknowledge that investments in new healthcare therapies equivalent to A-syn include very excessive dangers and people dangerous funding {dollars} get to decide on between healthcare therapies that undergo 15+ years of fundamental analysis and costly medical trials and different alternatives that may be launched in lower than a 12 months.
Of paramount concern, the FDA’s regulatory scheme has had two deleterious results on fund-raising. First, the FDA overhang has dried up curiosity in angel and enterprise capital investing in potential therapies equivalent to A-syn. The end result has been a Valley of Loss of life between fundamental analysis and drug growth. Second, even when the preliminary Valley might be crossed by authorities grants or non-profit donations, the FDA regulatory scheme places an unlimited burden on firms to lift scores of thousands and thousands of {dollars} for prolonged medical trials that face an unsure regulatory end result.
NIH/NINDS haven’t acknowledged that even with none direct position in fundraising, the FDA dominates the fund-raising course of. For instance, roughly 90% of fundraising for R&D relies on claims tied to regulatory milestones. Traders are well-aware of the challenges of the FDA approval course of and it curbs investor curiosity.
Even in fundamental analysis, the FDA has had a big affect on scientific progress. For the tutorial entrepreneur, early growth of an efficient regulatory plan might be the distinction between success and failure. Due to this fact, regulatory technique turns into a essential element of the innovation course of.
HHS should additionally acknowledge that the FDA has safety-first tradition and a not-invented-here syndrome on the subject of any proposed modifications to its processes.
The answer to those challenges, partially, entails HHS imposing a relaxed regulatory scheme for PD. For instance, the FDA must be excludedfrom Part 1 and Part 2 trials and from offering any steering to researchers previous to Part 3 medical trials. Such a change will pace growth, unleash innovation, and enhance early-stage fund-raising.
Second, to enhance efficiency of the analysis endeavors, NINDS must be tasked to develop and handle a proper, hub-and-spoke, communications community amongst all stakeholders concerned in PD analysis. ClinicalTrials.gov doesn’t fulfill this requirement as a result of it incorporates deceptive info.
Facilitating common exchanges of knowledge, knowledge sharing, and collaboration ought to assist to maximise the impression of analysis efforts and keep away from duplication of labor. For the funding group, a partition within the hub with investment-related info would assist to construct a bridge over the Valley of Loss of life and produce extra funding to potential therapies such alpha-synuclein.
This investor-related partition of the communications workplace ought to usually be housed by MBAs (moderately than by Ph.D.’s) who’re centered on speaking excessive worth analysis endeavors with the not-so-subtle intent of fomenting an curiosity in investments. NIH ought to think about hiring an funding banking agency to help in organising the investor-related element of this info community.
The third suggestion for change is that NIH ought to convene a really small group of consultants engaged on PD analysis to determine the three most-likely-to-succeed paths to a treatment. It ought to make sure that these paths have satisfactory personnel and enough analysis {dollars} for completion. Progress must be monitored regularly.
Lastly, I ought to point out that the Michael J. Fox Basis has executed a wonderful job on numerous necessary points and must be a serious a part of any restructure going ahead. For instance, HHS may outsource the communications hub to MJFF.
The underside line is that each one parts of the PD {industry}, together with the FDA, have to be on the identical web page when it comes to discovering a treatment for PD inside an inexpensive period of time given current assets whether or not it’s with alpha synuclein or different therapies. Such has not been the case with A-syn so far, and equally, we have now witnessed that your entire analysis effort for PD has underperformed – and can proceed to underperform – within the absence of corrective motion.
The Lengthy and Tortured Historical past of Alpha-Synuclein and Parkinson’s Illness
Preface
This research tracks the decades-long journey to harness alpha-synuclein as a remedy for Parkinson’s illness. The writer affords three key modifications wanted to beat the underlying challenges.
A Fast Begin for Alpha-Synuclein R&D
Within the mid-1990’s, Parkinson’s affected person advocacy teams had develop into impatient by the absence of any main therapeutic advances within the 25 years since L-dopa had been authorized for Parkinson’s illness (PD).
The Director of Nationwide Institute of Neurological Issues and Stroke (NINDS) arrange a workshop in August 1995 that featured scientists with experience in human genetics who may open novel avenues for PD analysis.
One such scientist, Robert Nussbaum, made the next remarks on the workshop:
“…discovering genes accountable for familial Parkinson’s must be useful for understanding all types of the illness. Strategies now out there ought to enable researchers to seek out the genes accountable for familial Parkinson’s illness in a comparatively quick time.”
Two years later in 1997, Spillantini et al. confirmed that alpha-synuclein (A-syn) was a serious contributor of irregular clusters of proteins within the mind, not solely in sufferers with synuclein mutations however, extra importantly, in sufferers with sporadic Parkinson’s illness as effectively.
As Nussbaum had predicted, progress had occurred quickly. President Clinton in his 1998 State of the Union tackle, stated:
“Take into consideration this, your entire retailer of human data now doubles each 5 years. Within the 1980’s, scientists recognized the gene inflicting cystic fibrosis. It took 9 years. Final 12 months scientists situated the gene that causes Parkinson’s illness in solely 9 days.”
The NIH is Requested to Take a Management Function
Shortly after President Clinton’s name to motion, a Senate Committee requested the Nationwide Institutes of Well being (NIH) to develop a coordinated effort to benefit from promising alternatives in PD analysis.
In response, the NIH and the Nationwide Institute of Neurological Illness and Stroke (NINDS) held a serious planning assembly that included all parts of the PD group. The group’s suggestions shaped the idea of a five-year PD Analysis Agenda.
The Analysis Agenda was codified in a complete 42-page report that lined all facets of analysis from higher understanding the illness, to creating new analysis capabilities, to creating new therapies, and to enhancing the analysis course of.
Noting the “exceptional paradigm shift in Parkinson’s illness analysis” from the invention of the consequences of alpha-synuclein, the report acknowledged that:
“New insights into the position of synucleins within the pathobiology of Parkinson’s illness would speed up discovery of simpler therapies and supply recent analysis alternatives to advance our understanding of Parkinson’s illness”.
NIH invested almost $1 billion from FY 2000 to FY 2004 to implement the PD Analysis Agenda. A-syn analysis could be funded out of the funds allotted to the classes of Genetics and Epidemiology, with each classes focused to obtain about 15% of the general spending.
Total, there have been 19 broad classes with spending authorizations, together with $32.7 million allotted to Program Administration and Route.
When the PD Analysis Agenda reached the tip of its 5-year span, NINDS sponsored a second PD Summit which was held in June 2005. It introduced collectively an industry-wide consortium to evaluate the progress over the earlier 5 years and to develop future instructions for PD analysis.
The individuals generated greater than fifty particular suggestions. NIH thought-about these plans and the unmet objectives from earlier efforts and developed a 3-year Plan.
A significant focus of that Plan was to determine and intervene with the causes of PD. As reiterated within the 2006 Plan:
“…Understanding the position of alpha-synuclein could allow methods to selectively block the dangerous results related to this protein as a novel strategy to remedy of PD”.
NINDS famous that:
“Whereas PD isn’t a uncommon or orphan illness, different extra prevalent illnesses equivalent to stroke, weight problems and diabetes supply significantly bigger “markets” for drug therapies than does PD. Thus, pharmaceutical firms have primarily centered on medicinal chemistry and alterations of current PD or different neurological medicine (e.g., dopamine agonists) moderately than investing in new medicine.”
In essence, NINDS acknowledged the monetary conundrum of drug growth for A-syn and different PD therapies, however seemed to academia to resolve the issue by its grant program.
Missing success from the efforts of the 2006 Plan, NINDS organized one other convention in January 2014 known as: Parkinson’s Illness 2014: Advancing Analysis, Bettering Lives. The aim of this initiative was to determine vital challenges and to spotlight the very best priorities for advancing analysis.
Thirty-one suggestions have been supplied. The abstract of the convention included the High 3 priorities for medical analysis, translational analysis, and fundamental analysis. Below fundamental analysis, priorities 1 and a pair of associated to alpha-synuclein.
On condition that the work specified for A-syn analysis was nonetheless at an early stage of fundamental analysis in 2014, it’s clear that a big hole existed between the earlier NINDS priorities for A-syn and what was delivered.
Personal Pursuits Lastly Transfer Ahead with Alpha-Synuclein
Recognizing the persevering with lack of progress and the necessity for funding, the Michael J. Fox Basis introduced a $10-million “Ken Griffin Alpha-synuclein Imaging Competitors” in 2019 to spur growth of a essential and elusive imaging analysis instrument for Parkinson’s illness.
In March 2023, MJFF introduced that the three preliminary Alpha-synuclein imaging competitors groups — AC Immune, Mass Basic Brigham and Merck— made large developments within the growth of various alpha-synuclein tracer strategies.
MJFF awarded Merck a further $1.5 million to proceed the work and produce its instrument to life. The primary-in-human medical trial of its alpha-synuclein PET tracer started in 2023.
Moreover, after greater than twenty years of fundamental analysis, 5 personal analysis firms filed purposes with the FDA and have initiated early-stage PD trials.
- Neuropore Therapies and UCB are collaborating on an oral small molecule, which goals to forestall the formation of alpha-synuclein clusters.
- Prothena Biosciences, at the side of Roche, is testing a humanized anti-alpha-synuclein antibody.
- Biogen is investigating one other monoclonal antibody in opposition to alpha-synuclein.
- AFFiRiS, an Austrian biotech firm, is testing an alpha-synuclein vaccine. AC Immune has lately introduced the acquisition of all of AFFiRiS’ property and underlying mental property associated to its vaccine candidates concentrating on a-syn.
- Vaxxinity makes use of an immunotherapy candidate codenamed UB–312 to focus on poisonous types of aggregated α-synuclein within the mind to combat Parkinson’s. Its Chairman lately stated that: “Our findings counsel UB-312 may rework Parkinson’s care, providing hope for improved outcomes with a disease-modifying remedy”.
As with all R&D initiatives, there are lots of remaining challenges within the growth of A-syn therapies earlier than reaching the market. However, assuming that a minimum of one of many 5 on-going trials shall be profitable, we will count on a remedy using A-syn shall be authorized by the FDA inside the subsequent 5-8 years. The web impact is that the general growth window between A-syn’s discovery in 1997 and its software to sufferers could be roughly 35 years – assuming that the analysis goes comparatively easily from right here.
Given its efficiency so far, the view from NIH concerning PD analysis is:
“… Our failures in bringing therapies to the purpose line are because of remaining massive gaps in data of the underlying biology that causes and drives the illness. As we fill in these gaps, the possibilities of success will improve. Among the gaps we find out about, others we solely discover out about when the science opens one other door”.
Why Has This Analysis Taken So Lengthy?
With the good thing about hindsight, we will level to 2 areas that accounted for the best obstacles to progress – focus and assets.
In studying the PD analysis plans and studies from 2000, 2006 and 2014, it seems that NINDS threw every thing it knew about PD into the hopper. There have been a whole bunch of suggestions, initiatives and so-called priorities. However a key issue of success in analysis is having a workforce of motivated scientists with the required expertise, data and pondering potential to resolve a finely-honed query.
There merely are usually not sufficient nice minds to trace down all the “to do’s” within the three NINDS PD analysis plans. Additionally, communications and networking are necessary parts of scientific development, but the aptitude to community with the widespread participation within the small grants program was missing.
The implication of utilizing the time period “focus” is that it comes with the project of accountability and accountability if the precedence doesn’t get executed. There seems to be little outdoors oversight of the effectivity and effectiveness of the analysis {dollars} that have been utilized on A-syn or different PD analysis initiatives. If something, NIH appears content material with the output.
Lastly, NIH/NINDS knew there was a funding drawback in crossing the Valley of Loss of life from fundamental analysis to medical trials, however these organizations fell again to their consolation zone, specifically small grants to academicians. This technique didn’t produce the required outcomes.
A Higher Strategy
In 1998 and thereafter, alpha-synuclein wanted a swat workforce of top-flight researchers together with a dedication for added funds because the challenge progressed out of fundamental analysis and thru the requisite medical trials.
To handle the shortcomings so far, the Division of Well being and Human Companies (HHS) ought to step in and 1) slender the PD analysis precedence checklist to the highest candidates, 2) require the institution of a sturdy communications community for sharing info and three) chill out the FDA laws for PD to assist degree the fund-raising taking part in subject.
Particularly, HHS/NIH/NINDS should acknowledge that investments in new healthcare therapies equivalent to A-syn include very excessive dangers and people dangerous funding {dollars} get to decide on between healthcare therapies that undergo 15+ years of fundamental analysis and costly medical trials and different alternatives that may be launched in lower than a 12 months.
Of paramount concern, the FDA’s regulatory scheme has had two deleterious results on fund-raising. First, the FDA overhang has dried up curiosity in angel and enterprise capital investing in potential therapies equivalent to A-syn. The end result has been a Valley of Loss of life between fundamental analysis and drug growth. Second, even when the preliminary Valley might be crossed by authorities grants or non-profit donations, the FDA regulatory scheme places an unlimited burden on firms to lift scores of thousands and thousands of {dollars} for prolonged medical trials that face an unsure regulatory end result.
NIH/NINDS haven’t acknowledged that even with none direct position in fundraising, the FDA dominates the fund-raising course of. For instance, roughly 90% of fundraising for R&D relies on claims tied to regulatory milestones. Traders are well-aware of the challenges of the FDA approval course of and it curbs investor curiosity.
Even in fundamental analysis, the FDA has had a big affect on scientific progress. For the tutorial entrepreneur, early growth of an efficient regulatory plan might be the distinction between success and failure. Due to this fact, regulatory technique turns into a essential element of the innovation course of.
HHS should additionally acknowledge that the FDA has safety-first tradition and a not-invented-here syndrome on the subject of any proposed modifications to its processes.
The answer to those challenges, partially, entails HHS imposing a relaxed regulatory scheme for PD. For instance, the FDA must be excludedfrom Part 1 and Part 2 trials and from offering any steering to researchers previous to Part 3 medical trials. Such a change will pace growth, unleash innovation, and enhance early-stage fund-raising.
Second, to enhance efficiency of the analysis endeavors, NINDS must be tasked to develop and handle a proper, hub-and-spoke, communications community amongst all stakeholders concerned in PD analysis. ClinicalTrials.gov doesn’t fulfill this requirement as a result of it incorporates deceptive info.
Facilitating common exchanges of knowledge, knowledge sharing, and collaboration ought to assist to maximise the impression of analysis efforts and keep away from duplication of labor. For the funding group, a partition within the hub with investment-related info would assist to construct a bridge over the Valley of Loss of life and produce extra funding to potential therapies such alpha-synuclein.
This investor-related partition of the communications workplace ought to usually be housed by MBAs (moderately than by Ph.D.’s) who’re centered on speaking excessive worth analysis endeavors with the not-so-subtle intent of fomenting an curiosity in investments. NIH ought to think about hiring an funding banking agency to help in organising the investor-related element of this info community.
The third suggestion for change is that NIH ought to convene a really small group of consultants engaged on PD analysis to determine the three most-likely-to-succeed paths to a treatment. It ought to make sure that these paths have satisfactory personnel and enough analysis {dollars} for completion. Progress must be monitored regularly.
Lastly, I ought to point out that the Michael J. Fox Basis has executed a wonderful job on numerous necessary points and must be a serious a part of any restructure going ahead. For instance, HHS may outsource the communications hub to MJFF.
The underside line is that each one parts of the PD {industry}, together with the FDA, have to be on the identical web page when it comes to discovering a treatment for PD inside an inexpensive period of time given current assets whether or not it’s with alpha synuclein or different therapies. Such has not been the case with A-syn so far, and equally, we have now witnessed that your entire analysis effort for PD has underperformed – and can proceed to underperform – within the absence of corrective motion.
Steve Zecola bought his net software and internet hosting enterprise when he was identified with Parkinson’s illness twenty three years in the past. Since then, he has run a consulting apply, taught in graduate enterprise faculty, and exercised extensively
#Lengthy #Tortured #Historical past #AlphaSynuclein #Parkinsons #Illness #Well being #Care #Weblog
https://thehealthcareblog.com/weblog/2024/03/29/the-long-and-tortured-history-of-alpha-synuclein-and-parkinsons-disease/