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.