Investigating the role of Amyloid Precursor-Like Protein 2 in Motor Neurone Disease

Abstract

Motor neurone disease (MND) is a fatal human neurodegenerative disorder. The most common form of MND is amyotrophic lateral sclerosis (ALS). MND is characterised by the progressive destruction of motor neurons in the central nervous system which causes muscle weakness, muscle atrophy, paralysis and ultimately death. The sporadic forms of the disease account for the majority of patients, and 5-10% of MND cases are inherited (familial MND) (Marin et al., 2017). Both sporadic and familial MND share similar clinical and pathological features, suggesting common molecular mechanisms of degeneration. Among the familial MND patients approximately 20% possess a mutation in the SOD1 gene encoding for the enzyme Cu/Zn superoxide dismutase (Rosen et al., 1993). There are more than 170 different SOD1 gene mutations described, and the majority are missense substitutions resulting in a toxic gain of enzyme function (http://alsod.iop.kcl.ac.uk/). Transgenic mouse models over-expressing mutant forms of the human SOD1 gene replicate key pathological symptoms seen in MND patients and are widely used to study MND. Despite progress in deciphering the molecular mechanisms of this disease, the cause and modulation of MND remains unclear.

The Amyloid Precursor Protein (APP), is well-known for its association with Alzheimer's Disease, and it has been shown to be a modulator of MND. APP protein expression levels were increased in the spinal cords from MND patients as well as in SOD1 transgenic mice at symptomatic stage of the disease (Koistinen et al., 2006; Rabinovich-Toidman et al., 2015). The resultant SOD1-G93A:APP-/- mice from the cross breeding between APP homozygous deletion and SOD1-G93A transgenic mice (overexpress human SOD1 gene with G93A familial mutation) showed significant decrease in MND pathogenesis and reduced disease progression (Bryson et al., 2012). The SOD1-G93A:APP-/- mice also displayed significantly ameliorated muscle contractility, improved neuromuscular junction innervation and decreased motor neuron loss. Taken together these findings suggest an important role for APP in MND pathophysiology.

APP is part of a gene family that includes the amyloid precursor-like protein 1 (APLP1) and amyloid precursor-like protein 2 (APLP2) genes. To understand if other APP-family members modulated MND we investigated the role of APLP2 in the SOD1-G37R transgenic mouse model. We found a significant sex-dependent increase in the expression of APLP2 protein in the spinal cord of the SOD1-G37R mice. To test if APLP2 gene expression can modulate disease outcomes in MND we crossed the SOD1-G37R and APLP2 knockout (KO) mice to generate the SOD1:APLP2+/- and SOD1:APLP2-/- lines. We found the lack of APLP2 expression improved motor performance and extend survival in a sex-dependent manner. The molecular basis for APLP2’s actions identified effects on muscle physiology and synaptic function at the neuromuscular junction.

Taken together, our novel results demonstrate there are sex-dependent differences in the SOD1 mouse model, and this is affected by APLP2 expression. These data extend the modulatory role by the amyloid precursor protein family in MND, and identify the APP-family as an important target for further investigation into the cause and regulation of MND.