MSA: From basic mechanisms to experimental therapeutics

Heras‐Garvin, Antonio; Stefanova, Nadia

doi:10.1016/j.parkreldis.2020.01.010

Cited by 16 publications

(18 citation statements)

References 193 publications

(305 reference statements)

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“…[27][28][29][30][31][32][33][34][35][36][37][38][39] Based on this evidence and the results from preclinical studies, numerous ongoing clinical trials are focused on targeting or modulating α-syn oligomerization and aggregation. 6 In particular, the use of small molecules that modulate α-syn accumulation presents many advantages such as their high oral bioavailability, blood-brain barrier penetration, ability to act inside cells, 40 and promising therapeutic potential in preclinical models of α-synucleionopathies by reducing α-syn inclusions, neurodegeneration and improving motor function. [7][8][9][10][11][12][13] We show that the small molecule ATH434, a novel quinazolinone inhibitor of iron-mediated α-syn protein accumulation, 11 reduces GCI-like inclusions and α-syn oligomeric species in MSA mice.…”

Section: Discussionmentioning

confidence: 99%

ATH434 Reduces α‐Synuclein‐Related Neurodegeneration in a Murine Model of Multiple System Atrophy

et al. 2021

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A BS TRACT: Background: Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by aggregated α-synuclein (α-syn) in oligodendrocytes and accompanied by striatonigral and olivopontocerebellar degeneration and motor symptoms. Key features of MSA are replicated in the PLP-α-syn transgenic mouse, including progressive striatonigral degeneration and motor deterioration. There are currently no approved treatments for MSA. ATH434 is a novel, orally bioavailable brain penetrant small molecule inhibitor of α-syn aggregation. Objectives: To characterize ATH434 for disease modification in a mouse model of MSA. Methods: Six-month-old PLP-α-syn mice (MSA mice) were ATH434-treated (ATH434 in food) or untreated (normal food) for 6 months. Motor behavior and numbers of nigral and striatal neurons were evaluated. α-syn aggregates and oligomers were quantified by immunohistochemical and western blot analyses. Microglial activation and neuroinflammation were assessed by histological and molecular analyses. Ferric iron in the Substantia nigra was evaluated with the Perls method.Results: ATH434-treated mice demonstrated preservation of motor performance in MSA mice that was associated with neuroprotection of nigral and striatal neurons. The rescue of the phenotype correlated with the reduction of α-syn inclusions and oligomers in animals receiving ATH434. ATH434-treated mice exhibited significantly increased lysosomal activity of microglia without increased pro-inflammatory markers, suggesting a role in α-syn clearing. ATH434-treatment was associated with lower intracellular nigral iron levels. Conclusions: Our findings demonstrate the beneficial disease-modifying effect of ATH434 in oligodendroglial α-synucleinopathy on both the motor phenotype and neurodegenerative pathology in the PLP-α-syn transgenic mouse and support the development of ATH434 for MSA.

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Section: Discussionmentioning

confidence: 99%

ATH434 Reduces α‐Synuclein‐Related Neurodegeneration in a Murine Model of Multiple System Atrophy

et al. 2021

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“…Given PD's shared pathophysiological basis with MSA (i.e., both are synucleinopathies), it will be interesting to follow current developments in MSA as treatments may also be effective in PD. α-syn aggregation inhibitors (e.g., Anle138b, CLR01, PBT-434, and VX-765), passive immunization (rec7), and α-syn degradation enhancers (e.g., rapamycin/ sirolimus) have been investigated for MSA; for a review, see Heras-Garvin and Stefanova [29].…”

Section: Gene Therapymentioning

confidence: 99%

Emerging Targeted Therapeutics for Genetic Subtypes of Parkinsonism

2020

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In recent years, a precision medicine approach, which customizes medical treatments based on patients’ individual profiles and incorporates variability in genes, the environment, and lifestyle, has transformed medical care in numerous medical fields, most notably oncology. Applying a similar approach to Parkinson’s disease (PD) may promote the development of disease-modifying agents that could help slow progression or possibly even avert disease development in a subset of at-risk individuals. The urgent need for such trials partially stems from the negative results of clinical trials where interventions treat all PD patients as a single homogenous group. Here, we review the current obstacles towards the development of precision interventions in PD. We also review and discuss the clinical trials that target genetic forms of PD, i.e., GBA-associated and LRRK2-associated PD.

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Section: Futures Perspectives In α-Syn Research and Therapymentioning

confidence: 99%

“…Most of these therapeutic strategies are currently under evaluation in human clinical trials (Heras-Garvin and Stefanova, 2020 ). Unfortunately, some of them have not shown ability to slow or halt disease progression (Heras-Garvin and Stefanova, 2020 ). The distinct efficacies observed between preclinical studies, based on in vitro and in vivo models, and the data from human studies could be explained by the neurobiological differences among species, but may be a consequence of current limitations to recruit patients at early stages of the disease, when significant neurodegeneration and motor symptoms are not yet present, to misdiagnosis and to the absence of specific biomarkers for α-syn.…”

Section: Futures Perspectives In α-Syn Research and Therapymentioning

confidence: 99%

From Synaptic Protein to Prion: The Long and Controversial Journey of α-Synuclein

Heras‐Garvin

Stefanova

2020

Front. Synaptic Neurosci.

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Since its discovery 30 years ago, α-synuclein (α-syn) has been one of the most studied proteins in the field of neuroscience. Dozens of groups worldwide have tried to reveal not only its role in the CNS but also in other organs. α-syn has been linked to several processes essential in brain homeostasis such as neurotransmitter release, synaptic function, and plasticity. However, despite the efforts made in this direction, the main function of α-syn is still unknown. Moreover, α-syn became a protein of interest for neurologists and neuroscientists when mutations in its gene were found associated with Parkinson's disease (PD) and even more when α-syn protein deposits were observed in the brain of PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) patients. At present, the abnormal accumulation of α-syn constitutes one of the pathological hallmarks of these disorders, also referred to as α-synucleinopathies, and it is used for post-mortem diagnostic criteria. Whether α-syn aggregation is cause or consequence of the pathogenic events underlying α-synucleinopathies remains unclear and under discussion. Recently, different in vitro and in vivo studies have shown the ability of pathogenic α-syn to spread between cells, not only within the CNS but also from peripheral locations such as the gut, salivary glands, and through the olfactory network into the CNS, inducing abnormal misfolding of endogenous α-syn and leading to neurodegeneration and motor and cognitive impairment in animal models. Thus, it has been suggested that α-syn should be considered a prion protein. Here we present an update of what we know about α-syn function, aggregation and spreading, and its role in neurodegeneration. We also discuss the rationale and findings supporting the hypothetical prion nature of α-syn, its weaknesses, and future perspectives for research and the development of disease-modifying therapies.

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MSA: From basic mechanisms to experimental therapeutics

Cited by 16 publications

References 193 publications

ATH434 Reduces α‐Synuclein‐Related Neurodegeneration in a Murine Model of Multiple System Atrophy

ATH434 Reduces α‐Synuclein‐Related Neurodegeneration in a Murine Model of Multiple System Atrophy

Emerging Targeted Therapeutics for Genetic Subtypes of Parkinsonism

From Synaptic Protein to Prion: The Long and Controversial Journey of α-Synuclein

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