Excess Lipin enzyme activity contributes to TOR1A recessive disease and DYT-TOR1A dystonia

Abstract

TOR1A/TorsinA mutations cause two incurable diseases: a recessive congenital syndrome that can be lethal, and a dominantly-inherited childhood-onset dystonia (DYT-TOR1A). TorsinA has been linked to phosphatidic acid lipid metabolism in Drosophila melanogaster. Here we evaluate the role of phosphatidic acid phosphatase (PAP) enzymes in TOR1A diseases using induced pluripotent stem cell-derived neurons from patients, and mouse models of recessive Tor1a disease. We find that Lipin PAP enzyme activity is abnormally elevated in human DYT-TOR1A dystonia patient cells and in the brains of four different Tor1a mouse models. Its severity also correlated with the dosage of Tor1a/TOR1A mutation. We assessed the role of excess Lipin activity in the neurological dysfunction of Tor1a disease mouse models by interbreeding these with Lpin1 knock-out mice. Genetic reduction of Lpin1 improved the survival of recessive Tor1a disease-model mice, alongside suppressing neurodegeneration, motor dysfunction, and nuclear membrane pathology. These data establish that TOR1A disease mutations cause abnormal phosphatidic acid metabolism, and suggest that approaches that suppress Lipin PAP enzyme activity could be therapeutically useful for TOR1A diseases.

Flexibility of a mammalian lipidome — insights from mouse lipidomics

“…Lipidomics has successfully been applied to study disease and disease-related mechanisms in many different indications. Among these are neurological disorders [Bosch-Queralt et al, 2021, Cascalho et al, 2020, liver disease [Parker et al, 2019] and cancer [Bi et al, 2019, Peck et al, 2016, Saliakoura et al, 2020, resulting in the identification of potential drug targets involved in lipid metabolism [Matsushita et al, 2021]. A primary model for these studies is the mouse Mus musculus.…”

TorsinA restoration in a mouse model identifies a critical therapeutic window for DYT1 dystonia

“…Changes not amenable to torsinA repletion likely include ChI degeneration, as initiating torsinA replacement after ChI loss is ineffective. An association between prevention of ChI degeneration and behavioral rescue has been demonstrated in torsinA LOF models (44,45), further supporting this connection. Striatal dysfunction secondary to ChI loss and dysfunction likely causes additional abnormalities of connectivity and function within and beyond the striatum, and failure to restore torsinA in these other neural elements may in part account for the incomplete motor rescue we observe.…”

Dystonia-specific mutations in THAP1 alter transcription of genes associated with neurodevelopment and myelin

“…59 Our results extend these observations further to human disease-specific variation and suggest that a complex interplay of dysregulated lysosomal sphingolipid metabolism, disrupted oligodendrocyte differentiation, and altered myelin formation and/or maintenance may contribute to the molecular and cellular mechanisms underlying THAP1 disease. [81][82][83][84] Although overt demyelination has not been specifically documented in dystonia, neuroimaging studies have reported white matter abnormalities in multiple forms of the disease, including: (1) syndromes associated with genetic variation in TOR1A, THAP1, SGCE, TAF1, KMT2B, and COL6A3 20,69,[85][86][87][88][89] ; and (2) idiopathic cases of cervical dystonia, writer's cramp, laryngeal dystonia, and blepharospasm. [90][91][92][93] The mechanisms underlying these disturbances in white matter tracts are not known, and further investigation is needed to determine if they reflect common defects in any of the pathways perturbed by genetic variation in THAP1.…”