Therapeutic approaches in Parkinson's disease and related disorders

Abstract

The lack of effective therapies for neurodegenerative disorders is one of the most relevant challenges of this century, considering that, as the global population ages, the incidence of these type of diseases is quickly on the rise. Among these disorders, synucleinopathies, which are characterized by the abnormal accumulation and spreading of the synaptic protein alpha-synuclein in the brain, already constitute the second leading cause of parkinsonism and dementia in the elderly population. Disorders with alpha-synuclein accumulation include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Numerous therapeutic alternatives for synucleinopathies are being tested in pre-clinical models and in the clinic; however, only palliative treatments addressing the dopaminergic deficits are approved to date, and no disease-modifying options are available yet. In this article, we provide a brief overview of therapeutic approaches currently being explored for synucleinopathies, and suggest possible explanations to the clinical trials outcomes. Finally, we propose that a deeper understanding of the pathophysiology of synucleinopathies, together with a combination of therapies tailored to each disease stage, may lead to better therapeutic outcomes in synucleinopathy patients. Synucleinopathies, neurodegenerative disorders characterized by the abnormal accumulation of the protein alpha-synuclein, constitute the second leading cause of parkinsonism and dementia in the elderly population, however, no disease-modifying options are available yet. In this review, we summarize the therapeutic approaches currently being explored for synucleinopathies, suggest possible explanations to the clinical outcomes, and propose areas of further therapeutic improvement. This article is part of a special issue on Parkinson disease.

Figure 1. Disease-modifying and symptomatic approaches for the treatment of synucleinopathies

Disease-modifying therapies delay, stop or revert the progression of the neurodegenerative pathology by targeting α-syn accumulation (including α-syn synthesis, aggregation and clearance), mitochondrial dysfunction, loss of neurotrophic factors, neuroinflammation and/or neurodegeneration. Symptomatic approaches are aimed at managing the disease symptoms, which may include parkinsonism, ataxia, dementia and cognitive deficits, among others. On the right, we provide a brief summary of the recent disease-modifying and symptomatic approaches targeting different molecular mechanisms in synucleinopathies.