Abstract
Background: Gilles de la Tourette syndrome (GTS) is a neurodevelopmental condition characterized by motor and vocal tics. The underlying etiology remains largely unknown, and GTS is considered as a complex multifactorial disorder associated with effects of several genes in combination with environmental factors. The inner mitochondrial membrane peptidase, subunit 2 (IMMP2L) has been suggested as one of the susceptibility genes for GTS, and IMMP2L-deficient mouse and human cells show increased levels of mitochondrial oxidative stress and altered cell fate programming. Hence, a potential involvement of IMMP2L-induced mitochondrial dysfunction in GTS pathology is yet to be elucidated. To address this, we investigated mitochondrial function in a group of GTS patients with intragenic IMMP2L deletions and compared with GTS without IMMP2L deletions and healthy controls.Methods: Mitochondrial function in fibroblasts from GTS patients and non-GTS parents (with and without IMMP2L deletions) compared to healthy controls were evaluated by measuring mitochondrial superoxide production, mitochondrial membrane potential, mitochondrial mass, and mitochondrial respiration. In addition, we evaluated apoptosis and senescence.Results: None of the mitochondrial parameters assessed in this study were significantly distinctive when comparing GTS patients with and without IMMP2L deletions against healthy controls or parents with or without IMMP2L deletions, and we did not observe altered cell programming.Conclusion: This study suggests that IMMP2L deletions do not lead to a substantial general mitochondrial dysfunction in GTS fibroblasts. Assessing a large cohort of controls and patients of similar age and gender would possibly reveal small differences in mitochondrial function. However, it is possible that IMMP2L variants affect mitochondrial function during specific instances of stress stimuli or in brain regions suggested to be affected in GTS.
Highlights
Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder, characterized by sudden, repetitive, non-rhythmic movements or sounds, referred to as tics
The following considerations were made for the inclusion of family members: [1] inclusion of two asymptomatic mothers without deletions in the control group would ensure similar mitochondrial DNA background when comparing fibroblasts with and without IMMP2L deletions; [2] inclusion of the parents with a deletion and without a GTS diagnosis would minimize the effect of the background variation in the nuclear genome on mitochondrial function, as half of the genetic material in the nuclear genome is identical between child–parent
The subjects investigated in this study were divided into three groups: [1] seven individuals with IMMP2L deletions (IMMP2L1–7), where four of them were clinically diagnosed with GTS (P1, P2, P5, and P6) and three of them were parents without a GTS diagnosis; [2] three GTS patients without IMMP2L deletions (TS 1–3); and [3] four controls without any GTS symptoms including mothers of patients P1 and P6 (Table 1)
Summary
Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder, characterized by sudden, repetitive, non-rhythmic movements or sounds, referred to as tics. One of the suggested GTS susceptibility genes is the inner mitochondrial membrane peptidase, subunit 2 (IMMP2L) [2,3,4,5,6,7], and structural variants involving this gene are implicated in other neurobiological/neuropsychiatric conditions including autism and ADHD [8,9,10,11]. Cerebellum is implied to have a role in motor function, and in cognitive and emotional processes, and its dysfunction is implicated both in movement disorders (e.g., ataxia and dystonia) and non-motor neuropsychiatric diseases (e.g., autism and ADHD) [12]. As mitochondrial dysfunction is linked to disorders affecting cerebellum [13], IMMP2L is a plausible susceptibility factor for neurobiological/neuropsychiatric disorders including GTS.
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