Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration
Paola Martinelli1, Veronica La Mattina, Andrea Bernacchia
1Division of Biochemistry and Genetics, Istituto Neurologico C. Besta, Milan, Italy.
Abstract:
The mitochondrial m-AAA protease has a crucial role in axonal development and maintenance. Human mitochondria possess two m-AAA protease isoenzymes: a hetero-oligomeric complex, composed of paraplegin and AFG3L2 (Afg3 like 2), and a homo-oligomeric AFG3L2 complex. Loss of function of paraplegin (encoded by the SPG7 gene) causes hereditary spastic paraplegia, a disease characterized by retrograde degeneration of cortical motor axons. Spg7(-/-) mice show a late-onset degeneration of long spinal and peripheral axons with accumulation of abnormal mitochondria. In contrast, Afg3l2(Emv66/Emv66) mutant mice, lacking the AFG3L2 protein, are affected by a severe neuromuscular phenotype, due to defects in motor axon development. The role of the homo-oligomeric m-AAA protease and the extent of cooperation and redundancy between the two isoenzymes in adult neurons are still unclear. Here we report an early-onset severe neurological phenotype in Spg7(-/-) Afg3l2(Emv66/+) mice, characterized by loss of balance, tremor and ataxia. Spg7(-/-) Afg3l2(Emv66/+) mice display acceleration and worsening of the axonopathy observed in paraplegin-deficient mice. In addition, they show prominent cerebellar degeneration with loss of Purkinje cells and parallel fibers, and reactive astrogliosis. Mitochondria from affected tissues are prone to lose mt-DNA and have unstable respiratory complexes. At late stages, neurons contain structural abnormal mitochondria defective in COX-SDH reaction. Our data demonstrate genetic interaction between the m-AAA isoenzymes and suggest that different neuronal populations have variable thresholds of susceptibility to reduced levels of the m-AAA protease. Moreover, they implicate impaired mitochondrial proteolysis as a novel pathway in cerebellar degeneration.
Insights
Mitochondrial m-AAA proteases are vital for neuron health. Combining mutations in paraplegin (SPG7) and AFG3L2 causes severe early-onset neurological disease and cerebellar degeneration, revealing genetic interactions.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- The mitochondrial m-AAA protease is essential for axonal development and maintenance.
- Two isoenzymes exist in human mitochondria: a hetero-oligomeric complex (paraplegin and AFG3L2) and a homo-oligomeric AFG3L2 complex.
- Loss of paraplegin causes hereditary spastic paraplegia, while AFG3L2 deficiency leads to motor axon defects.
Purpose of the Study:
- To investigate the role of the homo-oligomeric m-AAA protease and the interplay between the two isoenzymes in adult neurons.
- To characterize the neurological phenotype of combined paraplegin and AFG3L2 deficiency.
Main Methods:
- Generation and analysis of Spg7(-/-) Afg3l2(Emv66/+) mice.
- Assessment of neurological phenotypes, including motor function and balance.
- Histological examination of neuronal degeneration, particularly in the cerebellum.
- Mitochondrial analysis, including mtDNA stability and respiratory complex function.
Main Results:
- Spg7(-/-) Afg3l2(Emv66/+) mice exhibit early-onset severe neurological symptoms like ataxia and tremor.
- These mice show accelerated and worsened axonopathy compared to Spg7(-/-) mice.
- Prominent cerebellar degeneration, Purkinje cell loss, and reactive astrogliosis are observed.
- Affected mitochondria display mtDNA loss, unstable respiratory complexes, and structural abnormalities.
Conclusions:
- There is a genetic interaction between the two m-AAA protease isoenzymes.
- Different neuronal populations have varying susceptibility to reduced m-AAA protease levels.
- Impaired mitochondrial proteolysis is implicated as a novel mechanism in cerebellar degeneration.
