The HSP70 molecular chaperone is not beneficial in a mouse model of alpha-synucleinopathy.
BACKGROUND
Aggregation and misfolded alpha-synuclein is thought to be central in the pathogenesis of Parkinson's disease (PD). Heat-shock proteins (HSPs) that are involved in refolding and degradation processes could lower the aggregate load of alpha-synuclein and thus be beneficial in alpha-synucleinopathies.


RESULTS
We co-overexpressed human A53T point-mutated alpha-synuclein and human HSP70 in mice, both under the control of Thy1 regulatory sequences. Behavior read-outs showed no beneficial effect of HSP70 expression in mice. In contrast, motor coordination, grip strength and weight were even worse in the alpha-synucleinopathy model in the presence of HSP70 overexpression. Biochemical analyses revealed no differences in alpha-synuclein oligomers/aggregates, truncations and phosphorylation levels and alpha-synuclein localization was unchanged in immunostainings.


CONCLUSIONS
Overexpressing HSP70 in a mouse model of alpha-synucleinopathy did not lower the toxic load of alpha-synuclein species and had no beneficial effect on alpha-synuclein-related motor deficits.
Shimshek
Derya R
DR
Neuroscience Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland. derya.shimshek@novartis.com
Mueller
Matthias
M
Wiessner
Christoph
C
Schweizer
Tatjana
T
van der Putten
P Herman
PH
D000818:Animals; D001835:Body Weight; D004195:Disease Models, Animal; D015316:Genetic Therapy; D018840:HSP70 Heat-Shock Proteins / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D018737:Hand Strength; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D010300:Parkinson Disease / Q000473:pathology / Q000628:therapy*; D017354:Point Mutation; D017510:Protein Folding; D055503:Protein Multimerization; D017211:Treatment Failure; D051844:alpha-Synuclein / Q000008:administration & dosage / Q000009:adverse effects* / Q000235:genetics
D018840:HSP70 Heat-Shock Proteins; D051844:alpha-Synuclein