Abstract
Recent reports have identified rare, biallelic damaging variants of the AGTPBP1 gene that cause a novel and documented human disease known as childhood-onset neurodegeneration with cerebellar atrophy (CONDCA), linking loss of function of the AGTPBP1 protein to human neurodegenerative diseases. CONDCA patients exhibit progressive cognitive decline, ataxia, hypotonia or muscle weakness among other clinical features that may be fatal. Loss of AGTPBP1 in humans recapitulates the neurodegenerative course reported in a well-characterised murine animal model harbouring loss-of-function mutations in the AGTPBP1 gene. In particular, in the Purkinje cell degeneration (pcd) mouse model, mutations in AGTPBP1 lead to early cerebellar ataxia, which correlates with the massive loss of cerebellar Purkinje cells. In addition, neurodegeneration in the olfactory bulb, retina, thalamus and spinal cord were also reported. In addition to neurodegeneration, pcd mice show behavioural deficits such as cognitive decline. Here, we provide an overview of what is currently known about the structure and functional role of AGTPBP1 and discuss the various alterations in AGTPBP1 that cause neurodegeneration in the pcd mutant mouse and humans with CONDCA. The sequence of neuropathological events that occur in pcd mice and the mechanisms governing these neurodegenerative processes are also reported. Finally, we describe the therapeutic strategies that were applied in pcd mice and focus on the potential usefulness of pcd mice as a promising model for the development of new therapeutic strategies for clinical trials in humans, which may offer potential beneficial options for patients with AGTPBP1 mutation-related CONDCA.
Highlights
Childhood-onset neurodegeneration with cerebellar atrophy (CONDCA; OMIM 618276)is a recently identified, rare and severe autosomal recessive disease that affects the central and peripheral nervous systems
We review the variety of alterations in mAGTPBP1 in pcd mice and their relationships with the pathological variants of the hAGTPBP1 gene reported in CONDCA patients
The pathogenic events that occur in pcd mice, which harbours loss-of-function mutations in the AGTPBP1 gene, are described in-depth and summarised in the graphical abstract
Summary
Is a recently identified, rare and severe autosomal recessive disease that affects the central and peripheral nervous systems. Whole exome sequencing studies on CONDCA patients have identified different damaging biallelic variants of the AGTPBP1 gene [1,2,3,4], linking AGTPBP1 loss of function to human neurodegenerative diseases. More than 40 years ago, the Purkinje cell degeneration (pcd) mouse model, which harbours a mutation that is autosomal recessive and displays distinct neurological deficits, causing profound ataxic behaviour, was established [5]. The pcd mouse is an ideal animal model for investigating other probable but not yet characterised clinical alterations in patients with CONDCA. We focus on the potential usefulness of the pcd mouse model as a suitable model for the clinical assessment of new pharmacological strategies and therapies that may offer possible treatment options for patients with AGTPBP1 mutation-induced CONDCA
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