Neurodegeneration and motor dysfunction in a conditional model of Parkinson's disease.
Alpha-synuclein (alpha-syn) has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease. These disorders are characterized by various neurological and psychiatric symptoms based on progressive neuropathological alterations. Whether the neurodegenerative process might be halted or even reversed is presently unknown. Therefore, conditional mouse models are powerful tools to analyze the relationship between transgene expression and progression of the disease. To explore whether alpha-syn solely originates and further incites these alterations, we generated conditional mouse models by using the tet-regulatable system. Mice expressing high levels of human wild-type alpha-syn in midbrain and forebrain regions developed nigral and hippocampal neuropathology, including reduced neurogenesis and neurodegeneration in absence of fibrillary inclusions, leading to cognitive impairment and progressive motor decline. Turning off transgene expression in symptomatic mice halted progression but did not reverse the symptoms. Thus, our data suggest that approaches targeting alpha-syn-induced pathological pathways might be of benefit rather in early disease stages. Furthermore, alpha-syn-associated cytotoxicity is independent of filamentous inclusion body formation in our conditional mouse model.
Nuber
Silke
S
Department of Medical Genetics, University of Tuebingen, D-72076 Tuebingen, Germany.
Petrasch-Parwez
Elisabeth
E
Winner
Beate
B
Winkler
Jürgen
J
von Hörsten
Stephan
S
Schmidt
Thorsten
T
Boy
Jana
J
Kuhn
Melanie
M
Nguyen
Huu P
HP
Teismann
Peter
P
Schulz
Jörg B
JB
Neumann
Manuela
M
Pichler
Bernd J
BJ
Reischl
Gerald
G
Holzmann
Carsten
C
Schmitt
Ina
I
Bornemann
Antje
A
Kuhn
Wilfried
W
Zimmermann
Frank
F
Servadio
Antonio
A
Riess
Olaf
O
D000818:Animals; D006224:Cricetinae; D004195:Disease Models, Animal; D015987:Effect Modifier, Epidemiologic; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019957:Motor Skills Disorders / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*