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Life Without Paraplegin Synapses and Sisyphus: life without paraplegin Harris A. Gelbard J Clin Invest. 2004;113(2):185-187. https://doi.org/10.1172/JCI20783. Commentary The family of neurodegenerative diseases known as hereditary spastic parapareses have diverse genetic loci, yet there is a remarkable convergence in the neuropathologic and neurologic phenotype. A report describing the construction of a transgenic mouse with a deletion of a nuclear-encoded mitochondrial protein involved in the regulation of oxidative phosphorylation suggests that this family of diseases may reflect activation of a final common pathway involving synaptic dysfunction that progresses to destruction of the presynaptic nerve terminal and axon . Find the latest version: https://jci.me/20783/pdf Synapses and Sisyphus: defective, with a resultant decrease in mitochondrial complex I activity and life without paraplegin increased sensitivity to oxidant stress. Exogenous expression of wild-type Harris A. Gelbard paraplegin ameliorated both of these deficits. Finally, these investigators Departments of Neurology, Pediatrics, and Microbiology and Immunology; used yeast-complementation studies and the Center for Aging and Developmental Biology; to demonstrate that the paraplegin- University of Rochester Medical Center, Rochester, New York, USA AFG3L2 complex is functionally con- served with the yeast matrix-ATPase– The family of neurodegenerative diseases known as hereditary spastic associated activities protease, suggest- parapareses have diverse genetic loci, yet there is a remarkable conver- ing that this complex possesses prote- gence in the neuropathologic and neurologic phenotype. A report olytic activity. describing the construction of a transgenic mouse with a deletion of a nuclear-encoded mitochondrial protein involved in the regulation of The neuropathology of Spg7–/– mice oxidative phosphorylation suggests that this family of diseases may The Spg7–/– mice created by Ferreirin- reflect activation of a final common pathway involving synaptic dys- ha et al. (2) develop a neuropatholog- function that progresses to destruction of the presynaptic nerve termi- ic phenotype of a distal axonopathy nal and axon (see the related article beginning on page 231). characterized by swelling and degen- eration in spinal and peripheral J. Clin. Invest. 113:185–187 (2004). doi:10.1172/JCI200420783. axons. Although the axonopathy does not occur until 8 months of age, Hereditary spastic paraplegia (HSP) is a targeted deletion of Spg7 (Spg7–/–) Spg7–/– mice develop mitochondrial an umbrella term for a group of neu- that is associated with a clinical phe- abnormalities in their axons at 4.5 rodegenerative diseases with diverse notype strikingly similar to HSP. A months of age, a time when they clinical presentations and patterns of report by Settasatian et al. (3) charac- already exhibit motor deficits as evi- inheritance including autosomal dom- terized the Spg7 gene as a nuclear- denced by impaired ability to main- inant, autosomal recessive, and X- encoded mitochondrial metallopro- tain their balance on a rotating rod. linked. Indeed, 19 loci for HSP have tease that maps to chromosome These mitochondrial abnormalities been identified thus far (1). The unify- 16q24.3 and is the genetic locus for an include hypertrophy, concentric ing clinical symptom is progressive, autosomal recessive form of HSP. This cristae, herniations, and the appear- often severe, symmetric lower-extrem- metalloprotease, also known as para- ance of giant mitochondria. Mito- ity spasticity that, in isolation, is plegin, shares a high degree of homol- chondria with concentric cristae are known as pure HSP (PHSP) and, when ogy with yeast mitochondrial ATP- often seen in normal and pathologic accompanied by other deficits includ- dependent zinc metalloproteases, conditions with increased cellular ing impaired position sense and blad- including AFG3, RCA1, and YME1, metabolic activity. der disturbance, is known as compli- which have proteolytic and chaperone- Two additional striking findings cated HSP (CHSP). Despite the genetic like activities at the inner mitochondr- emerge from this study: at every age diversity inherent in this group of dis- ial membrane (4, 5). A report by Casari studied, the percentage of axons con- orders, considerable progress has been et al. (6) found a deletion mutation in taining abnormal mitochondria great- made in defining pathogenetic mech- paraplegin from familial kindred with ly exceeded the number of swollen or anisms for at least some forms of HSP. a 16q24.3 linkage, as well as several degenerated axons; and abnormal frameshift mutations in individuals mitochondria were present in synap- Paraplegin and HSP with CHSP and PHSP. Muscle biopsies tic terminals in the anterior horn of In this issue of the JCI, Ferreirinha et from two of these patients demon- the lumbar spinal cord at 4.5 months al. (2) describe the design and charac- strated defects in oxidative phospho- of age (2). Thus, abnormal mito- terization of a transgenic mouse with rylation, despite the fact that paraple- chondria in nerve terminals are the gin is not a protein associated with earliest neuropathologic hallmark of oxidative-phosphorylation abnormal- Spg7–/– mice. A diminution in ATP Address correspondence to: Harris A. Gelbard, Center for Aging and ities per se (7). Most recently, the work synthesis, however, is only apparent Developmental Biology, Aab Biomedical of Atorino et al. (8) suggests a possible relatively late in the course of the dis- Institute, University of Rochester Medical mechanism for this observation. These ease (23–26 months of age). Interest- Center, Box 645, 601 Elmwood Avenue, investigators demonstrate that para- ingly, the other functional deficit Rochester, New York 14642, USA. Phone: (585) 273-1473; Fax: (585) 506-1947; plegin coassembles with a homolo- studied in this report, retrograde E-mail: [email protected]. gous protein, AFG3L2, also present in transport in lumbar motor neurons, Conflict of interest: The author has declared the inner mitochondrial membrane, is not impaired in Spg7–/– mice until that no conflict of interest exists. into a high–molecular mass complex. 17 months of age. Nonstandard abbreviations used: hereditary –/– spastic paraplegia (HSP); pure HSP (PHSP); Using fibroblasts from patients with Thus, availability of the Spg7 complicated HSP (CHSP). HSP, they showed that this complex is model will allow investigators in the The Journal of Clinical Investigation | January 2004 | Volume 113 | Number 2 185 Figure 1 Hypothetical scheme for diminished complex I activity in presynaptic nerve terminals of Spg7–/– mice. (a) Schematic of a mitochondrion with a normal morphologic phenotype is depicted in a presynaptic nerve terminal, with an enlarged schematic of mitochondrial structure. With- in the inner mitochondrial membrane, the nuclear-encoded product of Spg7, paraplegin (PP), forms an approximately 900-kDa complex with AFG3L2 (AFG) (7). In this hypothetical scheme, this complex has proteolytic activity that is necessary for the normal physiologic activ- ity of NADH-ubiquinone oxidoreductase (complex I), such that the normal proton gradient is maintained between the mitochondrial matrix and the intermembrane space. This in turn allows for normal functioning of oxidative phosphorylation, and preservation of the mitochon- –/– drial membrane potential (∆ψm). However, in the absence of paraplegin in nerve terminals from an Spg7 mouse (b), an abnormal com- plex of AFG3L2 with a molecular weight of about 250 kDa (7) forms in the inner mitochondrial membrane that is unable to induce the nec- essary sequence of proteolytic events such that complex I has normal activity. This in turn results in a decrease in the proton gradient between the matrix and intermembrane space, with a presumed change in ∆ψm. As the animal ages, the net effect of diminished complex I activity in presynaptic nerve terminals is likely to be impairment of neurotransmitter release, pathologic generation of reactive oxygen species (ROS), and decreased retrograde transport of trophic substances. field to extend the observations of earliest neuropathologic hallmark of tion and normal function in affected Atorino et al. (8) regarding loss of the this transgene, suggests a possible pathways are doomed to failure in a complex formed by paraplegin and mechanism for the neurologic de- retrograde fashion. The finding that the murine homolog of AFG3L2 in ficits in these animals (Figure 1). As ATP production is decreased quite the inner mitochondrial membrane, the animal ages, synaptic activity late (23–26 months) in the course of and whether this loss results in simi- becomes progressively more compro- the animal’s lifespan does not neces- lar decreases in complex I activity and mised with increasing metabolic sarily confound this scheme, since susceptibility to oxidant stress. This is demands because of impaired com- there may be other compensatory especially intriguing in view of the plex I activity and increasing oxida- mechanisms at play to conserve ener- observation that complex I is pref- tive stress. This ultimately results in gy production in these animals. erentially affected by age-related a dying-back axonopathy, with disso- Regardless, there is a considerable changes in oxidative stress (9), with lution of the nerve terminal occur- temporal window of opportunity to the most significant dysfunction ring first, followed by destruction of rescue affected mitochondria in observed in synaptic mitochondria
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