Concurrent AFG3L2 and SPG7 mutations associated with syndromic parkinsonism and optic atrophy with aberrant OPA1 processing and mitochondrial network fragmentation

Abstract

Mitochondrial dynamics and quality control are crucial for neuronal survival and their perturbation is a major cause of neurodegeneration. m‐AAA complex is an ATP‐dependent metalloprotease located in the inner mitochondrial membrane and involved in protein quality control. Mutations in the m‐AAA subunits AFG3L2 and paraplegin are associated with autosomal dominant spinocerebellar ataxia (SCA28) and autosomal recessive hereditary spastic paraplegia (SPG7), respectively. We report a novel m‐AAA‐associated phenotype characterized by early‐onset optic atrophy with spastic ataxia and L‐dopa‐responsive parkinsonism. The proband carried a de novo AFG3L2 heterozygous mutation (p.R468C) along with a heterozygous maternally inherited intragenic deletion of SPG7. Functional analysis in yeast demonstrated the pathogenic role of AFG3L2 p.R468C mutation shedding light on its pathogenic mechanism. Analysis of patient's fibroblasts showed an abnormal processing pattern of OPA1, a dynamin‐related protein essential for mitochondrial fusion and responsible for most cases of hereditary optic atrophy. Consistently, assessment of mitochondrial morphology revealed a severe fragmentation of the mitochondrial network, not observed in SCA28 and SPG7 patients’ cells. This case suggests that coincidental mutations in both components of the mitochondrial m‐AAA protease may result in a complex phenotype and reveals a crucial role for OPA1 processing in the pathogenesis of neurodegenerative disease caused by m‐AAA defects.

Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7

“…25 The impaired balance of the different forms of OPA1 could be more severe in the presence of LOF variants leading to optic atrophy even in the absence of OPA1 mutations. 26 Furthermore, we confirm that the Ala510Val variant is the most common variant in patients (58.5%), showing a minor allele frequency of 0.5% in public databases, in agreement with other reports. 7,15,17,23,27 This variant was associated with a delayed onset of disease and a less complicated phenotype, i.e.…”

Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism

“…In this last patient, a family history of motorneuron disease (ALS) led the clinician to test for mutations in the SPG7 gene. Recently, both a single case of SPG7 presenting as a Parkinson's-like syndrome 11 and a patient with both AFG3L2 and SPG7 pathogenic variants and an early-onset optic atrophy with spastic ataxia and Ldopa-responsive parkinsonism have been reported 12 ; and in the Dutch study, a patient showed signs of parkinsonism, although this patient was under neuroleptics and the correlation was not as straightforward. 9 Therefore, the novel finding of parkinsonism as a frequent finding in the neurological examination of SPG7 patients, and the first report of a pure Pisa syndrome as initial presentation of underlying SPG7 disease, broadens the already wide spectrum of this disease.…”

“…1,4,9,10 The clinical spectrum of SPG7 disease continues to expand, and recently levodopa-responsive parkinsonism has been described in 2 patients. 11,12 Additionally, c.1529C>T (p.Ala510Val) variant in a heterozygous state has been found in 2 early-onset Parkinson's disease patients (EOPD). 13 SPG7 encodes paraplegin, a mitochondrial protein with a dual role as a metalloprotease responsible for assembling ribosomes and eliminating nonfunctional proteins in the mitochondria 14 and as a possible regulator of the mitochondrial permeability transition pore.…”

Loss of CHCHD2 and CHCHD10 activates OMA1 peptidase to disrupt mitochondrial cristae phenocopying patient mutations in vivo

“…The two best characterized stressors activating OMA1 are bioenergetic collapse and proteostatic stress following overload of quality control (QC) proteases (Head et al, 2009;Ehses et al, 2009). OMA1, for example, is activated following loss of AAA proteases YME1, AFG3L2, and SPG7, as well as scaffolding proteins, such as prohibitins and SLP-2, that organize YME1 and AFG3L2/SPG7, respectively, into microdomains in the inner membrane (Merkwirth et al, 2008;Ehses et al, 2009;Anand et al, 2014;Wai et al, 2016;Magri et al, 2018). Similarly, overload of QC proteases with aberrant mtDNA translation products in the setting of actininon treatment potently activates OMA1 prior to membrane potential collapse (Richter et al, 2015).…”

“…The peptidase OMA1 is activated by mitochondrial stressors to cleave the active long form of OPA1 (L-OPA1) from its membrane anchor, leading to mitochondrial fragmentation and alterations in cristae structure (Head et al, 2009;Ehses et al, 2009). L-OPA1 processing by OMA1 also occurs upon loss of quality control proteases, such as YME1, AFG3L2, and SPG7, as well as inner membrane scaffolding proteins of the SPFH family, namely, prohibitins and SLP-2, that organize quality control proteases within inner membrane microdomains (Anand et al, 2014;Wai et al, 2016;Merkwirth et al, 2008;Ehses et al, 2009;Magri et al, 2018). Thus, OMA1 provides an escape mechanism for cristae with failed of protein quality control, separating dysfunctional mitochondrial units from the reticulum for degradation by autophagy (MacVicar and Lane, 2014).…”