Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy.
BACKGROUND
Lewy body disease is a heterogeneous group of neurodegenerative disorders characterized by alpha-synuclein accumulation that includes dementia with Lewy bodies (DLB) and Parkinson's Disease (PD). Recent evidence suggests that impairment of lysosomal pathways (i.e. autophagy) involved in alpha-synuclein clearance might play an important role. For this reason, we sought to examine the expression levels of members of the autophagy pathway in brains of patients with DLB and Alzheimer's Disease (AD) and in alpha-synuclein transgenic mice.


RESULTS
By immunoblot analysis, compared to controls and AD, in DLB cases levels of mTor were elevated and Atg7 were reduced. Levels of other components of the autophagy pathway such as Atg5, Atg10, Atg12 and Beclin-1 were not different in DLB compared to controls. In DLB brains, mTor was more abundant in neurons displaying alpha-synuclein accumulation. These neurons also showed abnormal expression of lysosomal markers such as LC3, and ultrastructural analysis revealed the presence of abundant and abnormal autophagosomes. Similar alterations were observed in the brains of alpha-synuclein transgenic mice. Intra-cerebral infusion of rapamycin, an inhibitor of mTor, or injection of a lentiviral vector expressing Atg7 resulted in reduced accumulation of alpha-synuclein in transgenic mice and amelioration of associated neurodegenerative alterations.


CONCLUSIONS
This study supports the notion that defects in the autophagy pathway and more specifically in mTor and Atg7 are associated with neurodegeneration in DLB cases and alpha-synuclein transgenic models and supports the possibility that modulators of the autophagy pathway might have potential therapeutic effects.
Crews
Leslie
L
Department of Pathology, University of California San Diego, La Jolla, California, United States of America.
Spencer
Brian
B
Desplats
Paula
P
Patrick
Christina
C
Paulino
Amy
A
Rockenstein
Edward
E
Hansen
Lawrence
L
Adame
Anthony
A
Galasko
Douglas
D
Masliah
Eliezer
E
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002460:Cell Line; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D020961:Lewy Body Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D034622:RNA Interference; D015398:Signal Transduction; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D051844:alpha-Synuclein; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes