Pathogenic or protective? Neuropeptide Y in amyotrophic lateral sclerosis

Abstract

Neuropeptide Y (NPY) is an endogenous peptide of the central and enteric nervous systems which has gained significant interest as a potential neuroprotective agent for treatment of neurodegenerative disease. Amyotrophic lateral sclerosis (ALS) is an aggressive and fatal neurodegenerative disease characterized by motor deficits and motor neuron loss. In ALS, recent evidence from ALS patients and animal models has indicated that NPY may have a role in the disease pathogenesis. Increased NPY levels were found to correlate with disease progression in ALS patients. Similarly, NPY expression is increased in the motor cortex of ALS mice by end stages of the disease. Although the functional consequence of increased NPY levels in ALS is currently unknown, NPY has been shown to exert a diverse range of neuroprotective roles in other neurodegenerative diseases; through modulation of potassium channel activity, increased production of neurotrophins, inhibition of endoplasmic reticulum stress and autophagy, reduction of excitotoxicity, oxidative stress, neuroinflammation and hyperexcitability. Several of these mechanisms and signalling pathways are heavily implicated in the pathogenesis of ALS. Therefore, in this review, we discuss possible effects of NPY and NPY‐receptor signalling in the ALS disease context, as determining NPY’s contribution to, or impact on, ALS disease mechanisms will be essential for future studies investigating the NPY system as a therapeutic strategy in this devastating disease.

Alterations in leptin signaling in Amyotrophic Lateral Sclerosis (ALS)

“…Thus, in a situation of negative energy balance, such as the malnutrition observed in ALS, the expression of NPY and AgRP is normally increased and POMC expression decreased (Caron et al, 2018;Pedroso et al, 2016). Consistently, our data showed an up-regulation of NPY and AgRP in TDP-43 A315T mice at disease end-stage, as previously reported by others in ALS patients and several animal models (Clark et al, 2021;Vercruysse et al, 2016) and an overall decrease in POMC expression. These alterations in metabolic neuropeptides could partly explain the hypoglycemic state observed in TDP-43 A315T mice (Rodriguez et al, 2021).…”

Differential NPY-Y1 Receptor Density in the Motor Cortex of ALS Patients and Familial Model of ALS

“…At present, several selective NPY receptor agonists and antagonists have been developed and are widely used in research [61], while nasal delivery of the NPY peptide has been trialed for people with post-traumatic stress disorder [62]. Neuroprotection conferred by the NPY system has been demonstrated through modulation of neurotrophic pathways, neuroinflammation, pathogenic excitability, endoplasmic reticulum stress and mis-regulation of autophagy, mechanisms which have been implicated in the ALS pathogenesis (see review [26]).…”

“…Neuropeptide Y (NPY) signaling has been extensively associated with modulation of pre-and post-synaptic excitatory potentials across multiple brain regions, and has been shown to be neuroprotective by improving motor deficits and survival in models of neurodegenerative disease (see review [26]). Importantly, multiple studies have implicated the NPY system in the ALS disease pathogenesis.…”

Regulation of neuropeptide Y in body microenvironments and its potential application in therapies: a review

“…NPY binds to NPY receptors (NPYRs), which belong to the class A or rhodopsin-like G-protein coupled receptor family [ 1 , 7 , 8 ]. To date, five NPYRs (Y1R, Y2R, Y4R, Y5R, and Y6R) have been cloned from mammals, of which only four (hY1R, hY2R, hY4R, and hY5R) function in humans [ 9 ] (Table 1 ).…”