Valente, Valeria (2022) Unraveling the role of HIPK2 in neurodegeneration and pathogenesis of TDP-43-related ALS disease. [Tesi di dottorato]

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Abstract

Homeodomain interacting protein kinase 2 (HIPK2) is a key protein involved in cell proliferation and apoptosis, during embryonic development and adult life. The disruption of HIPK2 activity has been correlated to developmental anomalies and several diseases. Recently, HIPK2 has been reported to exert a crucial role in the physiology of the nervous system. In fact, the neurological phenotype shown by Hipk2 null mice is severely impaired and highly resembling a “motor neuron” disease such as ALS pathology. On the basis of these observations, we characterized the effects of Hipk2 loss on neuromuscular physiology and on the pathogenesis of ALS using in vivo and in vitro model systems. Interestingly, we found that HIPK2-KO mice show diffuse neuronal necrosis throughout the nervous system and morphological alterations of the neuromuscular junctions associated with poor mitochondrial proliferation. Our results clearly indicate that the deletion of Hipk2 is responsible for a myopathic phenotype in adult mice. Moreover, we found a strict interconnection between HIPK2 and TDP-43, which is one of the main pathological protein associated with both sporadic and familial ALS cases. Indeed, Hipk2 null mice show a strong delocalization of TDP-43 protein from the nucleus that accumulates in the cytosol of spinal motor neurons, as demonstrated by immunofluorescence and biochemical approaches. Consistently, silencing of Hipk2 expression in human derived neuroblastoma SH-SY5Y cells reproduces the same effect. Strikingly, the restoring of the expression of active Hipk2, but not of its kinase dead mutant, is responsible for the reestablishment of physiological TDP-43 subcellular distribution in HIPK2-interfered SH-SY5Y cells. Moreover, we found that Hipk2 deficient mice are more susceptible to develop symptoms of neurodegeneration and mislocalization of TDP-43 protein upon treatment with the neurotoxin L-BMAA. Taken together, these data unravel the functional crosstalk existing between HIPK2 and TDP-43 proteins and shed light on the putative protective role exerted by HIPK2 on nervous system homeostasis.

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