title: Rapamycin improves motor function, reduces 4-hydroxynonenal adducted protein in brain, and attenuates synaptic injury in a mouse model of synucleinopathy.
abstract: BACKGROUND
  Synucleinopathy is any of a group of age-related neurodegenerative disorders including Parkinson's disease, multiple system atrophy, and dementia with Lewy Bodies, which is characterized by α-synuclein inclusions and parkinsonian motor deficits affecting millions of patients worldwide. But there is no cure at present for synucleinopathy. Rapamycin has been shown to be neuroprotective in several in vitro and in vivo synucleinopathy models. However, there are no reports on the long-term effects of RAPA on motor function or measures of neurodegeneration in models of synucleinopathy.
  
  
  METHODS
  We determined whether long-term feeding a rapamycin diet (14 ppm in diet; 2.25 mg/kg body weight/day) improves motor function in neuronal A53T α-synuclein transgenic mice (TG) and explored underlying mechanisms using a variety of behavioral and biochemical approaches.
  
  
  RESULTS
  After 24 weeks of treatment, rapamycin improved performance on the forepaw stepping adjustment test, accelerating rotarod and pole test. Rapamycin did not alter A53T α-synuclein content. There was no effect of rapamycin treatment on midbrain or striatal monoamines or their metabolites. Proteins adducted to the lipid peroxidation product 4-hydroxynonenal were decreased in brain regions of both wild-type and TG mice treated with rapamycin. Reduced levels of the presynaptic marker synaptophysin were found in several brain regions of TG mice. Rapamycin attenuated the loss of synaptophysin protein in the affected brain regions. Rapamycin also attenuated the loss of synaptophysin protein and prevented the decrease of neurite length in SH-SY5Y cells treated with 4-hydroxynonenal.
  
  
  CONCLUSIONS
  Taken together, these data suggest that rapamycin, an FDA approved drug, may prove useful in the treatment of synucleinopathy.
authors: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors: Xiang
authors: X
authors: Bai
authors: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors: Margaret Chia-Ying
authors: MC
authors: Wey
authors: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care Network, San Antonio, TX, USA.
authors: Elizabeth
authors: E
authors: Fernandez
authors: Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|High Throughput Screening Facility, Center for Innovative Drug Discovery University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors: Matthew J
authors: MJ
authors: Hart
authors: Department of Epidemiology & Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors: Jonathan
authors: J
authors: Gelfond
authors: Department of Epidemiology & Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors: Alex F
authors: AF
authors: Bokov
authors: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors: Sheela
authors: S
authors: Rani
authors: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care Network, San Antonio, TX, USA; strong@uthscsa.edu.
authors: Randy
authors: R
authors: Strong
keywords: 4-hydroxynonenal (4-HNE); motor function; rapamycin; synaptic injury; synaptophysin; synucleinopathy