Beta-propeller protein-associated neurodegeneration (BPAN) as a genetically simple model of multifaceted neuropathology resulting from defects in autophagy

Catherine Hong Huan Hor, Bor Luen Tang
Reviews in the Neurosciences 2018 September 11
Autophagy is an essential and conserved cellular homeostatic process. Defects in the core and accessory components of the autophagic machinery would most severely impact terminally differentiated cells, such as neurons. The neurodevelopmental/neurodegenerative disorder β-propeller protein-associated neurodegeneration (BPAN) resulted from heterozygous or hemizygous germline mutations/pathogenic variant of the X chromosome gene WDR45, encoding WD40 repeat protein interacting with phosphoinositides 4 (WIPI4). This most recently identified subtype of the spectrum of neurodegeneration with brain iron accumulation diseases is characterized by a biphasic mode of disease manifestation and progression. The first phase involves early-onset of epileptic seizures, global developmental delay, intellectual disability and autistic syndrome. Subsequently, Parkinsonism and dystonia, as well as dementia, emerge in a subacute manner in adolescence or early adulthood. BPAN disease phenotypes are thus complex and linked to a wide range of other neuropathological disorders. WIPI4/WDR45 has an essential role in autophagy, acting as a phosphatidylinositol 3-phosphate binding effector that participates in autophagosome biogenesis and size control. Here, we discuss recent updates on WIPI4's mechanistic role in autophagy and link the neuropathological manifestations of BPAN's biphasic infantile onset (epilepsy, autism) and adolescent onset (dystonic, Parkinsonism, dementia) phenotypes to neurological consequences of autophagy impairment that are now known or emerging in many other neurodevelopmental and neurodegenerative disorders. As monogenic WDR45 mutations in BPAN result in a large spectrum of disease phenotypes that stem from autophagic dysfunctions, it could potentially serve as a simple and unique genetic model to investigate disease pathology and therapeutics for a wider range of neuropathological conditions with autophagy defects.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Trending Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"