title: A new role for α-synuclein in Parkinson's disease: Alteration of ER-mitochondrial communication.
abstract: Familial cases of Parkinson's disease (PD) can be associated with overexpression or mutation of α-synuclein, a synaptic protein reported to be localized mainly in the cytosol and mitochondria. We recently showed that wild-type α-synuclein is not present in mitochondria, as previously thought, but rather is located in mitochondrial-associated endoplasmic reticulum membranes. Remarkably, we also found that PD-related mutated α-synuclein results in its reduced association with mitochondria-associated membranes, coincident with a lower degree of apposition of endoplasmic reticulum with mitochondria and an increase in mitochondrial fragmentation, as compared with wild-type. This new subcellular localization of α-synuclein raises fundamental questions regarding the relationship of α-synuclein to mitochondria-associated membranes function, in both normal and pathological states. In this article, we attempt to relate aspects of PD pathogenesis to what is known about mitochondria-associated membranes' behavior and function. We hypothesize that early events occurring in dopaminergic neurons at the level of the mitochondria-associated membranes could cause long-term disturbances that lead to PD.
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Guardia-Laguarta
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Estela
authors.initials: E
authors.lastname: Area-Gomez
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA.|Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Schon
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Serge
authors.initials: S
authors.lastname: Przedborski
mesh_terms: D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein
keywords: MAM; Parkinson's Disease; α-synuclein