Alpha-synuclein, Proteotoxicity and Parkinson's Disease: Search for Neuroprotective Therapy

Abstract

Despite many limitations in our present knowledge of physiological and pathological functions of α-synuclein, it appears that this protein may be a target for the development of neuroprotective drugs against PD. This review has discussed many such potential drugs which prevent the expression, accumulation and aggregation of α-synuclein or its interactions with mitochondria or ER and thereby effectively abolish α-synuclein mediated toxicity in different experimental models.

Interaction of α-synuclein and Parkin in iron toxicity on SH-SY5Y cells: implications in the pathogenesis of Parkinson's disease

“…The role of α-synuclein in PD neurodegeneration has been intensively investigated in different animal and cell-based models [5][6][7]. Stereotaxic administration of viral vectors expressing wild or mutant α-synuclein gene or synthetic or naturally derived α-synuclein proteins in various forms into the substantia nigra or striatum of rodents or monkeys leads to dopaminergic neurodegeneration and locomotor deficits [5,[8][9][10][11]. Several cell-based models of neurodegeneration have demonstrated a toxic role for α-synuclein [12,13].…”

“…Several cell-based models of neurodegeneration have demonstrated a toxic role for α-synuclein [12,13]. This intrinsically disordered protein has the propensity to adopt a β-strand conformation and form oligomers of different sizes and finally fibrillar structures which accumulate as cytoplasmic inclusions called Lewy bodies (LBs) in degenerating neurons in PD [5,6]. However, it is not completely established which particular conformation or aggregation state or post-translational modification of α-synuclein or which particular interaction(s) of this protein with cellular components is central in PD neurodegeneration [5][6][7].…”

“…This intrinsically disordered protein has the propensity to adopt a β-strand conformation and form oligomers of different sizes and finally fibrillar structures which accumulate as cytoplasmic inclusions called Lewy bodies (LBs) in degenerating neurons in PD [5,6]. However, it is not completely established which particular conformation or aggregation state or post-translational modification of α-synuclein or which particular interaction(s) of this protein with cellular components is central in PD neurodegeneration [5][6][7]. Moreover, neither the endogenous factors responsible for increased accumulation of α-synuclein in sporadic PD brain are clearly identified, nor it is known how α-synuclein toxicity could be modulated by other familial PD-related proteins.…”

“…Moreover, neither the endogenous factors responsible for increased accumulation of α-synuclein in sporadic PD brain are clearly identified, nor it is known how α-synuclein toxicity could be modulated by other familial PD-related proteins. One important endogenous factor that could adversely affect neuronal death and aggravate α-synucleinopathy is iron, and iron accumulation in substantia nigra in PD brain is well-documented both by the analysis of post-mortem brain samples and by non-invasive magnetic resonance imaging during the course of the disease, and furthermore several genetic diseases affecting iron metabolism and storage often exhibit PD like features [5,[14][15][16]. Iron can contribute to neurodegeneration by producing reactive oxygen species (ROS), and further a distinct regulated cell death pathway called ferroptosis has been identified which requires iron and lipid peroxidation products [15,17].…”

“…Moreover, the oxidative stress induced by iron may also affect proteasomal function thereby hindering the degradation of accumulated α-synuclein, and in addition iron is known to promote α-synuclein aggregation [15,18]. Intra-cellular iron may also enhance α-synuclein protein expression through the predicted iron-responsive element in the 5'-UTR of α-synuclein mRNA [5]. Thus, iron could interact with PD pathogenic pathways like oxidative stress, α-synucleinopathy and neurodegeneration at multiple levels.…”