Multiple neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) are being suggested to have common cellular and molecular pathological mechanisms, characterized mainly by protein misfolding and aggregation. These large inclusions, most likely, represent an end stage of a molecular cascade; however, the soluble misfolded proteins, which take part in earlier steps of this cascade, are the more toxic players. These pathological proteins, which characterize each specific disease, lead to the selective vulnerability of different neurons, likely resulting from a combination of different intracellular mechanisms, including mitochondrial dysfunction, ER stress, proteasome inhibition, excitotoxicity, oxidative damage, defects in nucleocytoplasmic transport, defective axonal transport and neuroinflammation. Damage within these neurons is enhanced by damage from the nonneuronal cells, via inflammatory processes that accelerate the progression of these diseases. In this review, while acknowledging the hallmark proteins which characterize the most common NDDs; we place specific focus on the common overlapping mechanisms leading to disease pathology despite these different molecular players and discuss how this convergence may occur, with the ultimate hope that therapies effective in one disease may successfully translate to another.

Impaired mitochondrial function has been proposed as a causative factor in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), caused by motor neuron degeneration. Mutations in superoxide dismutase (SOD1) cause ALS and SOD1 mutants were shown to interact with the voltage-dependent anion channel 1 (VDAC1), affecting its normal function. VDAC1 is a multi-functional channel located at the outer mitochondrial membrane that serves as a mitochondrial gatekeeper controlling metabolic and energetic crosstalk between mitochondria and the rest of the cell and it is a key player in mitochondria-mediated apoptosis. Previously, we showed that VDAC1 interacts with SOD1 and that the VDAC1-N-terminal-derived peptide prevented mutant SOD1 cytotoxic effects. In this study, using a peptide array, we identified the SOD1 sequence that interacts with VDAC1. Synthetic peptides generated from the identified VDAC1-binding sequences in SOD1 directly interacted with purified VDAC1. We also show that VDAC1 oligomerization increased in spinal cord mitochondria isolated from mutant SOD1^G93A mice and rats. Thus, we used the novel VDAC1-specific small molecules, VBIT-4 and VBIT-12, inhibiting VDAC1 oligomerization and subsequently apoptosis and associated processes such as ROS production, and increased cytosolic Ca²⁺. VBIT-12 was able to rescue cell death induced by mutant SOD1 in neuronal cultures. Finally, although survival was not affected, VBIT-12 administration significantly improved muscle endurance in mutant SOD1^G93A mice. Therefore, VBIT-12 may represent an attractive therapy for maintaining muscle function during the progression of ALS.

Voltage-Dependent Anion Channel 1 (VDAC1) is a mitochondrial outer membrane protein that plays a crucial role in regulating cellular energy metabolism and apoptosis by mediating the exchange of ions and metabolites between mitochondria and the cytosol. Mitochondrial dysfunction and oxidative stress are central features of neurodegenerative diseases. The pivotal functions of VDAC1 in controlling mitochondrial membrane permeability, regulating calcium balance, and facilitating programmed cell death pathways, position it as a key determinant in the delicate balance between neuronal viability and degeneration. Accordingly, increasing evidence suggests that VDAC1 is implicated in the pathophysiology of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and others. This review summarizes the current findings on the contribution of VDAC1 to neurodegeneration, focusing on its interactions with disease-specific proteins, such as amyloid-β, α-synuclein, and mutant SOD1. By unraveling the complex involvement of VDAC1 in neurodegenerative processes, this review highlights potential avenues for future research and drug development aimed at alleviating mitochondrial-related neurodegeneration.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons. Mutations in the superoxide dismutase (SOD1) gene, causing protein misfolding and aggregation, were suggested as the pathogenic mechanisms involved in familial ALS cases. In the present study, we investigated the potential therapeutic effect of C4 and C5, two derivatives of the chemical chaperone 4-phenylbutyric acid (4-PBA). By combining in vivo and in vitro techniques, we show that, although C4 and C5 successfully inhibited amyloid aggregation of recombinant mutant SOD1 in a dose-dependent manner, they failed to suppress the accumulation of misfolded SOD1. Moreover, C4 or C5 daily injections to SOD1^G93A mice following onset had no effect on either the accumulation of misfolded SOD1 or the neuroinflammatory response in the spinal cord and, consequently, failed to extend the survival of SOD1^G93A mice or to improve their motor symptoms. Finally, pharmacokinetic (PK) studies demonstrated that high concentrations of C4 and C5 reached the brain and spinal cord but only for a short period of time. Thus, our findings suggest that use of such chemical chaperones for ALS drug development may need to be optimized for more effective results.