Calmodulin Binding Domains in Critical Risk Proteins Involved in Neurodegeneration

Abstract

Neurodegeneration leads to multiple early changes in cognitive, emotional, and social behaviours and ultimately progresses to dementia. The dysregulation of calcium is one of the earliest potentially initiating events in the development of neurodegenerative diseases. A primary neuronal target of calcium is the small sensor and effector protein calmodulin that, in response to calcium levels, binds to and regulates hundreds of calmodulin binding proteins. The intimate and entangled relationship between calmodulin binding proteins and all phases of Alzheimer’s disease has been established, but the relationship to other neurodegenerative diseases is just beginning to be evaluated. Risk factors and hallmark proteins from Parkinson’s disease (PD; SNCA, Parkin, PINK1, LRRK2, PARK7), Huntington’s disease (HD; Htt, TGM1, TGM2), Lewy Body disease (LBD; TMEM175, GBA), and amyotrophic lateral sclerosis/frontotemporal disease (ALS/FTD; VCP, FUS, TDP-43, TBK1, C90rf72, SQSTM1, CHCHD10, SOD1) were scanned for the presence of calmodulin binding domains and, within them, appropriate binding motifs. Binding domains and motifs were identified in multiple risk proteins, some of which are involved in multiple neurodegenerative diseases. The potential calmodulin binding profiles for risk proteins involved in HD, PD, LBD, and ALS/FTD coupled with other studies on proven binding proteins supports the central and potentially critical role for calmodulin in neurodegenerative events.

Protein Biomarkers Shared by Multiple Neurodegenerative Diseases Are Calmodulin-Binding Proteins Offering Novel and Potentially Universal Therapeutic Targets

“…The authors of that study found that serum NfL levels and APOE and GBA status combined with "previously validated clinical measures can provide a better prediction of several aspects of PD progression" than clinical measures. As discussed, APOE is a proven CaMBP and GBA is a putative one, with two canonical calcium-binding CaMBDs plus a single calcium-independent binding IQ motif [23].…”

“…CaM has multiple, critical functions in neurons where it regulates learning and memory, calcium homeostasis, synaptic signaling, neurotransmitter release, and neuroplasticity, among many other events. Its function in AD and other neurodegenerative diseases has been analyzed [8,23]. CaM has long been known as an essential protein that has changed little over its evolution.…”

Transmembrane Protein 175, a Lysosomal Ion Channel Related to Parkinson’s Disease

“…Other potential binding partners include APP [81], GPR37 [82], and two viral proteins (E5 and E5A) [83]. A Calmodulin Target Database scan revealed that TMEM175 contains a single calmodulin-binding domain [84], which indicates that TMEM175 may interact with calmodulin. Moreover, the STRING database (https://string-db.org/ (accessed on 23 December 2022)) was used to analyze the proteinprotein interaction networks of TMEM175 (Figure 3B) [85].…”

Phytochemical Interactions with Calmodulin and Critical Calmodulin Binding Proteins Involved in Amyloidogenesis in Alzheimer’s Disease

“…It regulates tau phosphorylation via two CaM-binding kinases CaMKII and cyclin-dependent kinase 5 (cdk5) and is a central regulatory element in synaptic events linked to learning and memory (e.g., CaMKII, PP2B) [ 26 ]. Finally, CaM binds to and regulates a number of CaMBPs involved in neuroinflammation and antioxidant functions, two events believed to be critical to the onset of AD as well as many other neurodegenerative diseases [ 27 ]. A large number of phytochemicals have been shown to have beneficial effects in the treatment of AD and there is accumulating evidence they may do so via their regulation of CaM and specific CaMBPs.…”