Dystrophin Dp71 and the Neuropathophysiology of Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is caused by frameshift mutations in the DMD gene that prevent the body-wide translation of its protein product, dystrophin. Besides a severe muscle phenotype, cognitive impairment and neuropsychiatric symptoms are prevalent. Dystrophin protein 71 (Dp71) is the major DMD gene product expressed in the brain and mutations affecting its expression are associated with the DMD neuropsychiatric syndrome. As with dystrophin in muscle, Dp71 localises to dystrophin-associated protein complexes in the brain. However, unlike in skeletal muscle; in the brain, Dp71 is alternatively spliced to produce many isoforms with differential subcellular localisations and diverse cellular functions. These include neuronal differentiation, adhesion, cell division and excitatory synapse organisation as well as nuclear functions such as nuclear scaffolding and DNA repair. In this review, we first describe brain involvement in DMD and the abnormalities observed in the DMD brain. We then review the gene expression, RNA processing and functions of Dp71. We review genotype-phenotype correlations and discuss emerging cellular/tissue evidence for the involvement of Dp71 in the neuropathophysiology of DMD. The literature suggests changes observed in the DMD brain are neurodevelopmental in origin and that their risk and severity is associated with a cumulative loss of distal DMD gene products such as Dp71. The high risk of neuropsychiatric syndromes in Duchenne patients warrants early intervention to achieve the best possible quality of life. Unravelling the function and pathophysiological significance of dystrophin in the brain has become a high research priority to inform the development of brain-targeting treatments for Duchenne.

Keywords: Apo-dystrophin-1; Dp71; Duchenne muscular dystrophy; Dystrophin; Neurodevelopment.

Fig. 1

Dp71 isoforms and preferred nomenclature. Dp71 splice isoforms are grouped according to their C-terminus. The d group contain exons 78 and 79, the f group lacks exon 78 and has an alternative exon 79 (79f), the e group contains part of intron 77 (i77) and lacks exons 78 and 79 and the g group isoform has a stop codon in exon 77. Their differential C-termini are illustrated and the location of dystroglycan and syntrophin-binding sites are indicated

Fig. 2

The Dp71 promoter region. Dp71 expression during neuronal differentitation is maintained by the combined action of Sp1 and AP2α as positive and negative regulators respectively. The transcription start site (+1) and Dp71 coding region are indicated

Fig. 3

The canonical non-neuronal role of Dp71. In the retina, Dp71 anchors aquaporin 4 (AQP4) and the inwardly rectifying potassium channel (Kir4.1) at the glial perivascular end-feet of Müller glial cells. α-syn, alpha-syntrophin

Fig. 4

A proposed synaptic function for Dp71. Dp71 organises glutamate receptor distribution at the postsynaptic density. The exact position and binding of Dp71 in relation to PSD-95 and particular receptors is unclear

Fig. 5

Multiple non-synaptic roles of Dp71. (1) Upon NGF-induced differentiation, Dp71d is phosphorylated by CaMKII and relocates to the nucleus where it forms a nuclear DAPC and may mediate nuclear responses during NGF signalling. In contrast, Dp71f moves to the cell surface and localises with the DAPC in areas such as the growth cone to play a role in neurite outgrowth. (2) Nuclear Dp71d binds to the DNA repair protein, RAD51. It also plays a role during cell division (3). (4) Dp71f is a facilitator of cell adhesion and binds to the β1-integrin adhesion complex. (5) Dp71 aids in cross-communication between the DAPC and the β1-integrin adhesion complex. Figure created with Biorender.com