Related Experiment Video
Updated: Jan 7, 2026
Real-Time Fluorescent Measurement of Synaptic Functions in Models of Amyotrophic Lateral Sclerosis
Published on: July 16, 2021
Engineered GM1 Intersects Between Mitochondrial and Synaptic Pathways to Ameliorate ALS Pathology
Federica Pilotto1,2, Tristan Dellazizzo Toth3,4, Silvano Bond3,4
1Institut Neuromyogène, Pathophysiology and genetics of the neuron and muscle, Inserm U1315, CNRS, Université Claude Bernard Lyon I, Lyon, France.
Abstract:
Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal condition marked by the degeneration of motor neurons. ALS has been linked to numerous genes with diverse biological roles, reflecting a highly intricate and multifaceted disease process. This diversity poses significant challenges in developing universally effective and bioavailable treatments. Advancing therapeutic strategies require uncovering molecular pathways that are major drivers of ALS. We conducted proteomic analyses of human iPSC-derived motor neurons carrying C9ORF72 mutations, alongside spinal ventral horns from mice with pathogenic C9orf72-mutations. This cross-species approach revealed disruptions in synaptic vesicle release, endoplasmic reticulum (ER) and mitochondrial stress responses as conserved ALS pathogenic mechanisms. Disease progression was associated with accumulation of cytotoxic protein aggregates and oxidative stress. We analyzed the potential of GM1, an established neuroprotective molecule, to reverse these pathogenic features. To enhance the pharmacokinetics of GM1, we developed Talineuren (TLN), a nanoliposome-based formulation of the active pharmaceutical ingredient GM1 ganglioside that improves its bioavailability. GM1 stabilized mitochondrial Ca2⁺ handling, improved energy metabolism, and alleviated ER stress, preventing protein aggregation and restoring cellular proteostasis and counteracted behavioral deficits in C9orf72 and SOD1-G93A mouse models. Together, these findings underscore the central, convergent role for cellular disruptions in ALS and position TLN as a promising therapeutic candidate.
Insights
Amyotrophic Lateral Sclerosis (ALS) involves motor neuron degeneration. A new nanoliposome formulation of GM1 ganglioside, Talineuren (TLN), shows promise by restoring cellular functions and counteracting deficits in ALS mouse models.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss.
- Genetic heterogeneity in ALS presents challenges for developing effective treatments.
- Identifying conserved molecular pathways is crucial for advancing ALS therapeutics.
Purpose of the Study:
- To investigate conserved pathogenic mechanisms in C9ORF72-linked ALS using a cross-species proteomic approach.
- To evaluate the neuroprotective potential of GM1 ganglioside and its nanoliposome formulation, Talineuren (TLN), in ALS models.
Main Methods:
- Proteomic analysis of human iPSC-derived motor neurons and mouse spinal cords with C9ORF72 mutations.
- Assessment of synaptic vesicle release, endoplasmic reticulum (ER) and mitochondrial stress responses.
- Pharmacokinetic evaluation and therapeutic efficacy testing of Talineuren (TLN) in C9ORF72 and SOD1-G93A mouse models.
Main Results:
- Conserved disruptions in synaptic vesicle release, ER, and mitochondrial stress were identified as key ALS mechanisms.
- Disease progression correlated with protein aggregate accumulation and oxidative stress.
- Talineuren (TLN) improved mitochondrial function, alleviated ER stress, prevented protein aggregation, and restored proteostasis.
- Talineuren (TLN) counteracted behavioral deficits in ALS mouse models.
Conclusions:
- Cellular disruptions, including ER and mitochondrial dysfunction, play a central role in ALS pathogenesis.
- Talineuren (TLN), a bioavailable formulation of GM1 ganglioside, demonstrates significant neuroprotective effects.
- Talineuren (TLN) represents a promising therapeutic candidate for ALS treatment.
