Mitochondrial <i>PITRM1</i> peptidase loss-of-function in childhood cerebellar atrophy

Langer, Yeshaya; Aran, Adi; Gülsüner, Süleyman; Libdeh, Bassam Abu; Renbaum, Paul; Brunetti, Dario; Teixeira, P. E.; Walsh, Tom; Zeligson, Sharon; Ruotolo, Roberta; Beeri, Rachel; Dweikat, Imad; Shahrour, Maher; Weinberg‐Shukron, Ariella; Zahdeh, Fouad; Baruffini, Enrico; Glaser, Elzbieta; King, Mary Claire; Levy‐Lahad, Ephrat; Zeviani, Massimo; Segel, Reeval

doi:10.1136/jmedgenet-2018-105330

Cited by 29 publications

(30 citation statements)

References 22 publications

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“…Despite this evidence, the causal link between mitochondrial demise and neurodegeneration still remains elusive. We have recently reported that pathogenic variants in the nuclear-encoded mitochondrial peptidase PITRM1 result in childhood-onset recessive cerebellar disease leading to a slowly progressive syndrome, characterized by spinocerebellar ataxia, mild intellectual disability, psychiatric manifestations, and cognitive decline 2, 3 . The clinical picture of these patients is unusual for mitochondrial disease, with a very slow progression of cognitive and psychiatric symptoms from childhood to their late sixties 2 .…”

Section: Discussionmentioning

confidence: 99%

“…However, mitochondria are often considered to be a secondary target, rather than the actual disease driver in these conditions. We have recently described three independent families carrying missense loss of function mutations in pitrilysin metallopeptidase 1 (PITRM1), resulting in an age-dependent, progressive, neurological syndrome 2, 3 . Patients suffer from progressive cerebellar dysfunction leading to cerebellar atrophy, and psychiatric manifestations including obsessive behavior, anger attacks, and psychosis 2, 3 .…”

Section: Introductionmentioning

confidence: 99%

“…We have recently described three independent families carrying missense loss of function mutations in pitrilysin metallopeptidase 1 (PITRM1), resulting in an age-dependent, progressive, neurological syndrome 2, 3 . Patients suffer from progressive cerebellar dysfunction leading to cerebellar atrophy, and psychiatric manifestations including obsessive behavior, anger attacks, and psychosis 2, 3 . Interestingly, some of these patients showed a deterioration of their cognitive functions with a slow progression till their late sixties 2, 3 .…”

Section: Introductionmentioning

confidence: 99%

“…Patients suffer from progressive cerebellar dysfunction leading to cerebellar atrophy, and psychiatric manifestations including obsessive behavior, anger attacks, and psychosis 2, 3 . Interestingly, some of these patients showed a deterioration of their cognitive functions with a slow progression till their late sixties 2, 3 . Human PITRM1, also known as presequence peptidase (hPreP), is a nuclear-encoded mitochondrial gene, expressed in a number of tissues, including muscles and different brain regions, e.g.…”

Section: Introductionmentioning

confidence: 99%

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Loss of function of the mitochondrial peptidase PITRM1 induces proteotoxic stress and Alzheimer’s disease-like pathology in human cerebral organoids

Ivanyuk

Pérez

Panagiotakopoulou

et al. 2020

Preprint

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Mutations in pitrilysin metallopeptidase 1 (PITRM1), a mitochondrial protease involved in mitochondrial precursor processing and degradation, result in a slow-progressive syndrome, characterized by cerebellar ataxia, psychotic episodes and obsessive behavior as well as cognitive decline. To investigate the pathogenetic mechanisms of mitochondrial presequence processing, we employed cortical neurons and cerebral organoids generated from PITRM1 knockout human induced pluripotent stem cells (iPSCs). PITRM1 deficiency strongly induced mitochondrial unfolded protein response (UPRmt) and enhanced mitochondrial clearance in iPSC-derived neurons. Furthermore, we observed increased levels of amyloid precursor protein and amyloid β in PITRM1 knockout neurons. However, neither cell death nor protein aggregates were observed in 2D iPSC-derived cortical neuronal cultures. On the contrary, cerebral organoids generated from PITRM1 knockout iPSCs spontaneously developed over time pathological features of Alzheimer’s disease (AD), including accumulation of protein aggregates, tau pathology, and neuronal cell death. Importantly, we provide evidence for a protective role of UPRmt and mitochondrial clearance against impaired mitochondrial presequence processing and proteotoxic stress. In summary, we propose a novel concept of PITRM1-linked neurological syndrome whereby defects of mitochondrial presequence processing induce an early activation of UPRmt that, in turn, modulates cytosolic quality control pathways. Thus our work supports a mechanistic link between mitochondrial function and common neurodegenerative proteinopathies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of function of the mitochondrial peptidase PITRM1 induces proteotoxic stress and Alzheimer’s disease-like pathology in human cerebral organoids

Ivanyuk

Pérez

Panagiotakopoulou

et al. 2020

Preprint

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“…Pitrm1 (encodes for PreP) knockout mice display embryonic lethality 10 . Furthermore, genetic defects in PreP are linked with human neurological disorders, e.g., cognitive disability/impairment and cerebellar atrophy 10,11 .…”

Section: Introductionmentioning

confidence: 99%

Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition

Liang¹,

Wijaya²,

Wei³

et al. 2020

Preprint

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Presequence protease (PreP), a 117 kDa mitochondrial M16C metalloprotease vital for mitochondrial proteostasis, degrades presequence peptides cleaved off from nuclear-encoded proteins and other aggregation-prone peptides, such as amyloid β (Aβ). PreP structures have only been determined in a closed conformation; thus, the mechanisms of substrate binding and selectivity remain elusive. Here, we leverage advanced vitrification techniques to overcome the preferential denaturation of one of two ~55 kDa homologous domains of PreP caused by air-water interface adsorption, and thereby elucidate cryoEM structures of three apo-PreP open states along with Aβ- and citrate synthase presequence-bound PreP at 3.3 Å-4.6 Å resolution. Together with integrative biophysical and pharmacological approaches, these structures reveal the key stages of the PreP catalytic cycle and how the binding of substrates or PreP inhibitor drives the rigid body motion of the protein for substrate binding and catalysis. Together, our studies provide key mechanistic insights into M16C metalloproteases for future therapeutic innovations.

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Mitochondrial proteases in human diseases

Gala

Vögtle

2021

FEBS Letters

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Mitochondria contain more than 1000 different proteins, including several proteolytic enzymes. These mitochondrial proteases form a complex system that performs limited and terminal proteolysis to build the mitochondrial proteome, maintain and control its functions or degrade mitochondrial proteins and peptides. During protein biogenesis presequence proteases cleave and degrade mitochondrial targeting signals to obtain mature functional proteins. Processing by proteases also exerts a regulatory role in modulation of mitochondrial functions and quality control enzymes degrade misfolded, aged or superfluous proteins. Depending on their different functions and substrates, defects in mitochondrial proteases can affect the majority of the mitochondrial proteome or only a single protein. Consequently, mutations in mitochondrial proteases have been linked to several human diseases. This review gives an overview of the components and functions of the mitochondrial proteolytic machinery and highlights the pathological consequences of dysfunctional mitochondrial protein processing and turnover.

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Mitochondrial PITRM1 peptidase loss-of-function in childhood cerebellar atrophy

Abstract: results in childhood-onset recessive cerebellar pathology. Severity of -related disease may be affected by the degree of impairment in cleavage of mitochondrial long peptides. Disruption and deletion of X linked regulatory segments may also contribute to severity.

Cited by 29 publications

References 22 publications

Loss of function of the mitochondrial peptidase PITRM1 induces proteotoxic stress and Alzheimer’s disease-like pathology in human cerebral organoids

Loss of function of the mitochondrial peptidase PITRM1 induces proteotoxic stress and Alzheimer’s disease-like pathology in human cerebral organoids

Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition

Mitochondrial proteases in human diseases

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