Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport

Abstract

In several neurodegenerative diseases, axonal degeneration occurs before neuronal death and contributes significantly to patients’ disability. Hereditary spastic paraplegia (HSP) is a genetically heterogeneous condition characterized by selective degeneration of axons of the corticospinal tracts and fasciculus gracilis. HSP may therefore be considered an exemplary disease to study the local programs mediating axonal degeneration. We have developed a mouse model for autosomal recessive HSP due to mutations in the SPG7 gene encoding the mitochondrial ATPase paraplegin. Paraplegin-deficient mice are affected by a distal axonopathy of spinal and peripheral axons, characterized by axonal swelling and degeneration. We found that mitochondrial morphological abnormalities occurred in synaptic terminals and in distal regions of axons long before the first signs of swelling and degeneration and correlated with onset of motor impairment during a rotarod test. Axonal swellings occur through massive accumulation of organelles and neurofilaments, suggesting impairment of anterograde axonal transport. Retrograde axonal transport is delayed in symptomatic mice. We speculate that local failure of mitochondrial function may affect axonal transport and cause axonal degeneration. Our data suggest that a timely therapeutic intervention may prevent the loss of axons

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

“…30 RSV has been proven to improve the overall metabolic health status in clinical trials for patients with metabolic disorders, 32 which may or may not be confirmed in currently ongoing clinical trials for AD and Friedreich ataxia (NCT01339884, NCT01504854, NCT00743743, NCT00678431). Therapeutic implications derived from this work may be potentially extended to other diseases such as multiple sclerosis, 65 amyotrophic lateral sclerosis 66 and some forms of HSP such as SPG7, 54 which share axonal degeneration as a primary component of clinical disability and oxidative stress/mitochondria impairment as the primary or early contributing pathogenic factors. Mouse strains.…”

Mitochondrial dynamics in the regulation of neuronal cell death

“…In addition to Paraplegin, the groups of de Strooper and Scorrano have shown that mice lacking PARL have reduced cleavage of Opa1, indicating a requirement for PARL activity in the maturation of Opa1 [96]. Comparing Opa1 processing and mitochondrial morphology between Opa1 and Paraplegin deficient mice [100] will show which protein is the major processor for Opa1. Parapelgin, however, has also been implicated in the proper ribosome assembly in mitochondria [101] and reduction of paraplegin can also induce complex 1 deficiency and sensitivity to oxidative stress [102].…”

Autocatalytic Processing of m-AAA Protease Subunits in Mitochondria

“…Primary MEFs were established from E14.5 embryos derived from intercrosses of time-mated Spg7 ϩ/ϩ or Spg7 Ϫ/Ϫ mice and immortalized by SV40 transformation (Ferreirinha et al, 2004). RNA interference (RNAi)-mediated down-regulation of gene expression was performed using specific Stealth RNAi and the nontargeting Stealth RNAi Negative Control (Invitrogen).…”

“…Paraplegin E575Q was processed as efficiently as wildtype paraplegin upon mitochondrial import (Supplemental Figure S1). To exclude a role of preexisting, endogenous paraplegin for maturation, we isolated mitochondria from liver derived from paraplegin-deficient Spg7 Ϫ/Ϫ mice (Ferreirinha et al, 2004). The absence of paraplegin within mitochondria did not impair the import and processing of 35 S-labeled paraplegin, which occurred to a similar extent in Spg7 ϩ/ϩ and Spg7 Ϫ/Ϫ liver mitochondria (Supplemental Figure S1).…”