The Neuroprotective Effect of Cdc42 Inhibition in the G93A Mutant hSOD1 Mouse Model of ALS

Cdc42 Inhibition in G93A-hSOD1 Amyotrophic Lateral Sclerosis: In Vitro and In Vivo Studies

Amyotrophic lateral sclerosis (ALS) is a highly progressive neurodegenerative disease affecting motor neurons (MNs) in the motor cortex, brain stem, and spinal cord. Patients ultimately succumb to muscle paralysis by mechanisms of MN axonal retraction, denervation from neuro-muscular junctions (NMJs), and neuronal apoptosis. Previous research has demonstrated that Rho family GTPases, Rac and Rho, are involved in mechanisms of neurite extension, retraction and cell survival, however it remains to be investigated whether Rho GTPase actin-cytoskeleton modulator, Cdc42, plays a role in ALS disease progression. In studying G93A-SOD1 NSC-34 motor neuronal cells treated with Cdc42 inhibitor, ZCL367, we identified that Cdc42 activation in disease-state neurons may be deleterious. Additionally, Cdc42 inhibitors, ZCL367 and high-dose ZCL279, appear to be neuroprotective against the selective degeneration of α-MNs in the ventral horn of G93A-hSOD1 transgenic (Tg) mice.

Targeting Mitochondrial Fission Produces Both Neuroprotective and Detrimental Effects in the SOD1 Mouse Model of Amyotrophic Lateral Sclerosis

Simple Summary Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, leading to progressive muscle weakness and severe muscle wasting. In addition to neuronal loss, increasing evidence suggests that problems in mitochondrial function, the process by which cells produce energy, may contribute to disease development and progression. In this study, we investigated the effects of Mdivi-1, a drug that inhibits mitochondrial fragmentation, in a mouse model of ALS. Treatment began before symptoms appeared in order to assess whether it could slow disease progression. Our findings showed that Mdivi-1 partially protected motor neurones in the spinal cord, but this did not result in improved motor performance. Moreover, treated animals developed more severe muscle wasting and changes in muscle fiber composition. We also observed cellular alterations associated with impaired neuromuscular function. Overall, these results highlight that mitochondrial dynamics play a complex and context-dependent role in the disease. A better understanding of these mechanisms will be important for developing more effective therapeutic strategies for ALS.

Cortistatin as a modulator of inflammatory and mitochondrial dysfunction in Huntington´s disease.

These results support cortistatin-based strategies as a promising disease-modifying therapeutic avenue for HD and related neurodegenerative disorders characterized by inflammatory activation and mitochondrial impairment.

HDAC6 inhibition alleviates mitochondrial trafficking in models of Charcot-Marie-Tooth disease type 2A

Charcot-Marie-Tooth disease (CMT) is a group of inherited progressive conditions affecting distal motor and sensory neurons, leading to muscle weakness, pain, and loss of sensation in limbs. CMT type 2A (CMT2A) is the most common form of axonal CMT and is associated with a more severe clinical manifestation. However, there are no treatments currently available. To investigate disease mechanisms and facilitate treatment discovery, we developed an in vitro model for CMT2A by introducing the patient-specific MFN2R94Q/+ variant into human embryonic stem cells (hESCs). Isogenic variant and wild-type hESCs differentiated into spinal motor neurons with similar efficiency and gave rise to functional motor neurons in vitro. However, MFN2R94Q/+ spinal motor neurons displayed impaired mitochondrial trafficking, resulting in altered distribution of mitochondria in axons. Unbiased quantitative proteomic profiling of the endogenous MFN2 interactome revealed dose-dependent remodelling by the R94Q variant across 412 proteins, highlighting candidate mechanisms in disease pathology. Importantly, we showed that mitochondrial trafficking defects could be alleviated by treatment with an HDAC6 inhibitor. Chemical inhibition of HDAC6 also rescued the motor phenotype in a zebrafish CMT2A model. Taken together, our study reveals a variant-specific insight into CMT2A disease mechanisms and confirms HDAC6 as a promising target for further therapeutic development.

Targeting TDP-43 in sporadic amyotrophic lateral sclerosis

FUS-driven zebrafish model of ALS identifies tribenzylamine as a candidate modulator of ALS-associated pathology.

Findings support the mtFUS zebrafish model as a useful platform for ALS drug discovery and identify tribenzylamine as a candidate modulator of ALS-associated phenotypes, with effects linked to transcriptomic remodeling and neuronally active sex steroid signaling.