Improvements in biophysical techniques such as Cryogenic-Electron Microscopy (Cryo-EM), and computational predictive models such as AlphaFold have advanced our ability to visualize protein structure and connect structure to biological function. However, intrinsically disordered proteins and protein regions (IDPs and IDRs) remain recalcitrant to these methods, contributing to the lack of knowledge regarding their roles in cellular regulation. While their significance has garnered appreciation in recent years, their inherent flexibility and functional promiscuity enable uniquely adaptable and diverse roles spanning signaling to cellular homeostasis that warrant greater investigation. Their ability to engage membranes under varying cellular conditions highlights one aspect of their adaptability. This characteristic is especially prominent in the context of neuronal signaling, where IDPs play diverse roles from synaptic vesical localization and fusion (a-synuclein and complexin) to cytoskeletal structure (tau and actin). Notably, IDPs are frequently implicated in neurological disorders, with genetic mutations and post-translational modifications (PTMs) associated with intracellular aggregation, aberrant function and disrupted signaling pathways. Here, we contribute to the illumination of the importance of IDPs in neuronal membrane interactions and highlight the mechanisms that drive their role in disease pathology. We provide mechanistic insight into the fundamental understanding of neuronal signaling through IDPs and their membrane and protein interactions through a multitude of projects. We investigate the regulation of neuronal G protein-couple receptor (GPCR) metabotropic glutamate receptors (mGluR) 2 & 3 through their membrane-interacting, intrinsically disordered Cterminal domains. We also investigate the interaction between post-synaptic density protein 95 (PSD-95), specifically its disordered N-terminus and guanylate kinase domain (GUK), and tau under disease conditions, as well as investigating the assembly of wild-type and PTM-mimetic mutations of tau alone and in the presence of membranes. Finally, we investigate amyloid fibril formation by the intrinsically disordered regions of mitochondrial paralog proteins coiled-helix coiled-helix domain containing proteins 10 and 2 (CHCHD10/D2), which are mutated in frontotemporal dementia, Parkinson’s disease and mitochondrial myopathy. Overall, this work contributes to the field’s understanding of the role of intrinsically disordered proteins/regions in neuronal and mitochondria regulation through membrane and protein interactions and provides insights into the regulation and dysfunction that occurs during diseases.