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Cherubini 2014 Abstract MiP2014

From Bioblast
Striatal deregulation of Cdk5 alters mitochondrial dynamics in Huntington’s disease.

Link: Mitochondr Physiol Network 19.13 - MiP2014

Cherubini M, Puigdellivol M, Alberch J, Gines S (2014)

Event: MiP2014

Huntington’s disease (HD) is characterized by motor disturbances associated with dysfunction and degeneration of the medium spiny neurons within the striatum [1,2]. The molecular mechanisms underlying striatal vulnerability are still unknown, but growing evidence suggests that mitochondrial dysfunction occurs during the pathogenesis of the disease [3]. We previously described that deregulation of cyclin-dependent kinase 5 (Cdk5), activity induced by mutant huntingtin, increases the susceptibility of striatal neurons to dopamine via D1 receptor activation [4]. Interestingly, Cdk5 has been shown to act as a mitochondrial regulator during neuronal apoptosis [5]. We investigated whether this aberrant Cdk5 signalling contributes to the striatal neurodegeneration by altering mitochondrial dynamics processes. We first observed that presence of striatal cells expressing mutant huntingtin (mHtt) increased mitochondrial fragmentation which worsens after dopaminergic stimuli. These mitochondrial defects can be widely rescued by Cdk5 inhibition with roscovitine or Cdk5 knockdown with siRNA transfection. Furthermore, we found that mHtt deregulates the levels and the subcellular distribution of fission/fusion proteins, while activation of D1 receptors promotes an increase of fission protein Drp1 levels and its translocation to the mitochondria. We demonstrated that mHtt-induced Cdk5 activation is involved in the deregulation of the Drp1 GTPase activity, since its inhibition prevents the aberrant activation of this fission protein. In summary, our findings support the hypothesis that Cdk5 plays a crucial role in mitochondrial defects involved in the striatal neurodegeneration in HD.

Labels: MiParea: mt-Structure;fission;fusion  Pathology: Neurodegenerative  Stress:Mitochondrial disease 

Tissue;cell: Nervous system 

Event: A2, P-flash  MiP2014 


1-Dep Biol Cellular, Immunologia Neurociències, Fac Medicina, Univ Barcelona; 2-Inst d´Investigacions Biomèdiques August Pi i Sunyer, Barcelona; 3-Centro Investig Bioméd Red sobre Enfermedades Neurodegenerativas; Spain. - [email protected]

References and acknowledgements

Supported by Ministerio de Innovación y Ciencia SAF2012-39142, CHDI Ministerio de Sanidad y Consumo (CIBERNED CB06/05/0054), Fundación Ramón Areces.

  1. Ferrante RJ, Kowall NW, Beal MF, Martin JB, Bird ED, Richardson EP Jr (1987) Morphologic and histochemical characteristics of a spared subset of striatal neurons in Huntington’s disease. J Neuropathol Exp Neurol 46: 12-27.
  2. Myers RH, Vonsattle JP, Stevens TJ, Cupples LA, Richardson EP, Martin JB, Bird ED (1988) Clinical and neuropathologic assesment of severity in Huntington’s disease. Neurology 38: 341-37.
  3. Damiano M, Galvan L, Déglon N, Brouillet E (2010) Mitochondria in Huntington’s disease. Biochim Biophys Acta 1802: 52-61.
  4. Paoletti P, Vila I, Rifé M, Lizcano JM, Alberch J, Ginés S (2008) Dopaminergic and glutamatergic signaling crosstalk in Huntington’s disease neurodegeneration: the role of p25/cyclin dependent kinase 5. J Neurosci 28: 10090-101.

5. Meuer K, Suppanz IE, Lingor P, Planchamp V, Göricke B, Fichtner L, Braus GH, Dietz GP, Jakobs S, Bähr M, Weishaupt JH (2007) Cyclin-dependent kinase 5 is an upstream regulator of mitochondrial fission during neuronal apoptosis. Cell Death Differ 14: 651-61.