Disease-modifying effects of metabolic perturbations in ALS/FTLD

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two fatal neurodegenerative disorders with considerable clinical, pathological and genetic overlap. Both disorders are characterized by the accumulation of pathological protein aggregates that contain a number of proteins, most notably TAR DNA binding protein 43 kDa (TDP-43). Surprisingly, recent clinical studies suggest that dyslipidemia, high body mass index, and type 2 diabetes mellitus are associated with better clinical outcomes in ALS. Moreover, ALS and FTLD patients have a significantly lower incidence of cardiovascular disease, supporting the idea that an unfavorable metabolic profile may be beneficial in ALS and FTLD. The two most widely studied ALS/FTLD models, super-oxide dismutase 1 (SOD1) and TAR DNA binding protein of 43 kDA (TDP-43), reveal metabolic dysfunction and a positive effect of metabolic strategies on disease onset and/or progression. In addition, molecular studies reveal a role for ALS/FTLD-associated proteins in the regulation of cellular and whole-body metabolism. Here, we systematically evaluate these observations and discuss how changes in cellular glucose/lipid metabolism may result in abnormal protein aggregations in ALS and FTLD, which may have important implications for new treatment strategies for ALS/FTLD and possibly other neurodegenerative conditions.

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“…Future research should encourage approaches that test convergent biologically plausible mechanisms. For example, the transactive response DNA binding protein 43 (TDP-43) has been implicated in the etiology of several aging-related neurodegenerative disorders, including PD [138], AD [127], ALS [86], frontotemporal dementia [18], and idiopathic late-onset dementia [123].…”

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“…Interestingly, ALS patients with high body mass index (BMI) have better prognosis than patient with BMI within the normal values. Moreover, obese individuals are less likely to develop ALS than individuals with average weight (Jawaid et al, 2018). However, BMI does not differentiate between fat or lean body mass.…”

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“…Other intriguing lines of research evaluated some metabolic parameters as disease-modifiers that can impact the clinical course in ALS. For example, recent investigations have shown that high-risk cardiovascular profiles such as a high body mass index (BMI) or diabetes mellitus type 2 might be protective for ALS patients and may act by delaying the onset and/or by slowing down clinical progression of the disease [79][80][81][82][83][84][85]. Altogether, these finding suggest that caution should be exercised when comorbidities and risk factors are evaluated as prognostic factor in such as complex diseases as ALS and FTD.…”

“…Altogether, these finding suggest that caution should be exercised when comorbidities and risk factors are evaluated as prognostic factor in such as complex diseases as ALS and FTD. In particular, a better characterization of the eventual association between the clinicopathological features of the patients and a particular metabolic disorder might be helpful to understand if and how metabolic disorders can influence the subcellular localization, aggregation, and phosphorylation of some of pathogenic proteins, or if the metabolic disorders might rather modulate the toxic effects downstream of these events [81]. In addition, these observations open potentially the way to nutrition, dietary supplements (in particular, antioxidant) and lifestyle interventions as potential strategies for modifying the course of the disease [86][87][88].…”