2. Academic Validation
  3. Alpha-synuclein in Parkinson's disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction

Alpha-synuclein in Parkinson's disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction

  • Cell Death Dis. 2023 Mar 1;14(3):176. doi: 10.1038/s41419-023-05672-9.
Paolo Calabresi # 1 2,  Alessandro Mechelli # 3,  Giuseppina Natale 4,  Laura Volpicelli-Daley 5,  Giulia Di Lazzaro # 6,  Veronica Ghiglieri # 6 7
Affiliations

Affiliations

  • 1 Sezione di Neurologia, Dipartimento di Neuroscienze, Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, 00168, Italy. [email protected].
  • 2 Neurologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy. [email protected].
  • 3 Dipartimento di Scienze Mediche e Chirurgiche, Istituto di Neurologia, Università "Magna Graecia", Catanzaro, Italy.
  • 4 Sezione di Neurologia, Dipartimento di Neuroscienze, Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, 00168, Italy.
  • 5 Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
  • 6 Neurologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy.
  • 7 Università Telematica San Raffaele, Rome, 00166, Italy.
  • # Contributed equally.
PMID: 36859484 DOI: 10.1038/s41419-023-05672-9
Abstract

Although the discovery of the critical role of α-synuclein (α-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 α-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 α-syn-related neurodegenerative disorders such as dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, and REM sleep behavior disorder. Furthermore, α-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 α-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 α-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.

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