Synuclein in the way of Mitochondrial transport and morphology

FALZONE T

Buenos Aires

Simposio; LATAM II; 2016

Sociedad Aregntina de Neurociencias

Parkinson?s Disease (PD), the second most prevalent neurodegenerative disorder, is characterized pathologically by a progressive loss of neurons and the accumulation of eosinophilic intracellular inclusions, termed Lewy bodies. The mayor component of these inclusions is α-synuclein (α-Syn), the first protein identified with dominant inheritance in familial PD (fPD). Later, a number of genes contributing to fPD have been identified from which Pink1, Parkin, DJ-1 and recently VPS35 have a direct role in controlling mitochondria, suggesting a mayor role of this pathway in disease progression. Although genetic mutations identified so far account for a small proportion of PD cases; there are pathological, pharmacological and genetic evidences supporting a common sporadic form of the disease (sPD) involving defects in neuronal mitochondrial homeostasis. Recently much attention has been dedicated to the possible role α-Syn has on mitochondrial pathologies, although, the mechanism by which α-Syn impairs mitochondrial function remains unknown. Stem cells are extremely promising for future cell replacement therapies, however, much need to be understood on the mechanisms leading into neurodegenerative diseases such as PD. Therefore, to test the role of α-Syn in mitochondrial morphology and PD associated pathologies we generated human models with α-Syn overexpression to study the axonal mitochondrial transport and morphology in human derived neurons from hESC or modified hiPSC. Genome editing of induced pluripotent stem cells opens a new path in the study of human pathologies. We provide novel evidence of a differential effect of α-Syn mutations in a common pathological pathway involving the control of mitochondrial fragmentation in human neurons. Moreover, by genome edition we uncover a new physiological role for α-Syn in the neuronal maintenance of mitochondrial size and distribution in axons. This knowledge provides an important contribution to the role that α-Syn could induce in the early neuropathology associated with the mitochondria in PD and highlight a potential novel therapeutic strategy for early intervention in PD, prior to neuronal loss and clinical manifestation of disease.