Alpha-synuclein research: defining strategic moves in the battle against Parkinson’s disease

Abstract

With the advent of the genetic era in Parkinson’s disease (PD) research in 1997, α-synuclein was identified as an important player in a complex neurodegenerative disease that affects >10 million people worldwide. PD has been estimated to have an economic impact of $51.9 billion in the US alone. Since the initial association with PD, hundreds of researchers have contributed to elucidating the functions of α-synuclein in normal and pathological states, and these remain critical areas for continued research. With this position paper the authors strive to achieve two goals: first, to succinctly summarize the critical features that define α-synuclein’s varied roles, as they are known today; and second, to identify the most pressing knowledge gaps and delineate a multipronged strategy for future research with the goal of enabling therapies to stop or slow disease progression in PD.

Pharmacological Modulation of Nrf2/HO-1 Signaling Pathway as a Therapeutic Target of Parkinson’s Disease

“…Parkinson’s disease (PD) is defined primarily as a movement disorder, with the typical symptoms being resting tremor, rigidity, bradykinesia, and postural instability ( Rai et al, 2020 ; Rai and Singh, 2020 ; Rai et al, 2021 ). PD is pathologically characterized by degeneration of nigrostriatal dopaminergic neurons and the presence of Lewy bodies (LBs), which mainly consist of misfolded α-synuclein, ubiquitin, Parkin, PTEN-induced kinase-1 (PINK1), and other proteins in the surviving neurons ( Rai et al, 2017 , 2019a ; Zahra et al, 2020 ; Oliveira et al, 2021 ). PD is the second most common age-related neurodegenerative disease, affecting more than 2% of the population older than 65 years old ( Aarsland et al, 2017 ).…”

“…Even though familial PD is the less frequent form as only 10% of cases comprise only a minor subset of the overall PD pool, these are of high relevance since they have provided extended information about pathogenesis ( Cuenca et al, 2018 ; Deng et al, 2018 ; Domingo and Klein, 2018 ). Since the first PD-associated substitution mutation of alanine in position 53 for threonine (A53T) in α-synuclein was identified more than 20 years ago ( Polymeropoulos et al, 1997 ), many other genes with Mendelian inheritance have been identified, and the number of PD-related genes as risk factors has exponentially increased ( Brás and Outeiro, 2021 ; Oliveira et al, 2021 ). Twenty-three loci and nineteen genes have been directly linked to the cause of genetic PD ( Deng et al, 2018 ) ( Table 1 ).…”

FKBP52 in Neuronal Signaling and Neurodegenerative Diseases: A Microtubule Story

“…Abnormalities in neuronal MT functions such as network stability and defective transport along the axon lead to brain diseases [127]. Indeed, alterations and aggregation of Tau and α-syn, which both impact MT assembly and signaling, are critical for the development of major neurodegenerative diseases called tauopathies including Alzheimer disease (AD) and synucleinopathies such as Parkinson disease (PD) respectively [128][129][130]. In these pathologies, the loss of MT function is accompanied by a gain of toxicity of Tau or α-syn both leading to neuronal death [131][132][133][134][135].…”

Examining the Toxicity of α-Synuclein in Neurodegenerative Disorders

“…As such, this brings into question whether the nitration of α-synuclein is a byproduct of PD pathogenesis or if it is a critical post-translational modification that occurs antecedently to the disease and is toxic. Nevertheless, the nitration of tyrosine has the potential to mimic certain aspects of mutated A30P, which could aid in the progression or initiation of PD [67].…”