Ph.D. Projects


Cerebellar degeneration by faulty protein quality control

The nuclear-encoded mitochondrial protein AFG3L2 forms homo-oligomeric and hetero-oligomeric complexes with its partner paraplegin in the inner mitochondrial membrane, named m-AAA proteases. These complexes are in charge of protein quality control by exerting chaperone activity on respiratory chain complexes and proteolytic degradation of misfolded proteins. Mutations of paraplegin cause a recessive form of hereditary spastic paraplegia (HSP) (1), while mutations in AFG3L2 have been recently associated to a dominant form of spinocerebellar ataxia (SCA28) (2).
Although AFG3L2 is ubiquitously expressed, it plays a key function in neurons. Mutant mouse models knockout for Afg3l2 display a severe neurological syndrome with marked impairment of motor axon and cerebellar development that leads to lethality at P16 (3). On the other hand, reduced Afg3l2 gene dosage causes progressive defects in motor coordination and balance due to degeneration of Purkinje cells in Afg3l2+/- mice. The presence of mitochondrial morphological alterations and a reduction in the activity of the respiratory chain demonstrate the organellar origin of the defect. These observations indicate that cerebellum is the neuronal tissue with the highest sensitivity to AFG3L2 dysfunction and that Afg3l2 haploinsufficient mouse recapitulates important features of SCA28 patients (4). However, the molecular basis of SCA 28 pathogenesis remains to be elucidated. This PhD project deals with the dissection of mitochondrial pathways in which AFG3L2 is involved. To achieve this goal, we will use integrate transcriptomic and proteomic approaches to profile mitochondria from cerebellum of Afg3l2 haploinsufficient mice at different stages of disease progression.
These analyses will provide important information about the mitochondria response to stimuli determined by reduced dosage of AFG3L2, thus greatly facilitating the comprehension of the pathogenetic mechanisms of this neurodegenerative disorder.

References:

(1) Casari G et al. Cell. 1998, 93(6): 973-83.
(2) DiBella D et al. Abstract, American Society of Human Genetics, 2008.
(3) Maltecca F et al. J Neurosci. 2008, 28(11): 2827-36.
(4) Maltecca F et al. J Neurosci. 2009, in press.