TY - JOUR
T1 - Alpha-synuclein in Parkinson's disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction
AU - Calabresi, Paolo
AU - Mechelli, Alessandro
AU - Natale, Giuseppina
AU - Volpicelli-Daley, Laura
AU - Di Lazzaro, Giulia
AU - Ghiglieri, Veronica
PY - 2023
Y1 - 2023
N2 - Although the discovery of the critical role of alpha-synuclein (alpha-syn) in the pathogenesis of Parkinson's disease (PD) is now twenty-five years old, it still represents a milestone in PD research. Abnormal forms of alpha-syn trigger selective and progressive neuronal death through mitochondrial impairment, lysosomal dysfunction, and alteration of calcium homeostasis not only in PD but also in other alpha-syn-related neurodegenerative disorders such as dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, and REM sleep behavior disorder. Furthermore, alpha-syn-dependent early synaptic and plastic alterations and the underlying mechanisms preceding overt neurodegeneration have attracted great interest. In particular, the presence of early inflammation in experimental models and PD patients, occurring before deposition and spreading of alpha-syn, suggests a mechanistic link between inflammation and synaptic dysfunction. The knowledge of these early mechanisms is of seminal importance to support the research on reliable biomarkers to precociously identify the disease and possible disease-modifying therapies targeting alpha-syn. In this review, we will discuss these critical issues, providing a state of the art of the role of this protein in early PD and other synucleinopathies.
AB - Although the discovery of the critical role of alpha-synuclein (alpha-syn) in the pathogenesis of Parkinson's disease (PD) is now twenty-five years old, it still represents a milestone in PD research. Abnormal forms of alpha-syn trigger selective and progressive neuronal death through mitochondrial impairment, lysosomal dysfunction, and alteration of calcium homeostasis not only in PD but also in other alpha-syn-related neurodegenerative disorders such as dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, and REM sleep behavior disorder. Furthermore, alpha-syn-dependent early synaptic and plastic alterations and the underlying mechanisms preceding overt neurodegeneration have attracted great interest. In particular, the presence of early inflammation in experimental models and PD patients, occurring before deposition and spreading of alpha-syn, suggests a mechanistic link between inflammation and synaptic dysfunction. The knowledge of these early mechanisms is of seminal importance to support the research on reliable biomarkers to precociously identify the disease and possible disease-modifying therapies targeting alpha-syn. In this review, we will discuss these critical issues, providing a state of the art of the role of this protein in early PD and other synucleinopathies.
KW - Biomarkers
KW - Parkinson
KW - Biomarkers
KW - Parkinson
UR - http://hdl.handle.net/10807/231305
U2 - 10.1038/s41419-023-05672-9
DO - 10.1038/s41419-023-05672-9
M3 - Article
SN - 2041-4889
VL - 14
SP - N/A-N/A
JO - CELL DEATH & DISEASE
JF - CELL DEATH & DISEASE
ER -