ALS/FTLD: experimental models and reality.

Area of Science:

• Neuroscience
• Neuropathology
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) involve motor neuron loss and brain atrophy, respectively.
• The most common forms feature neuronal inclusions of TAR DNA-binding protein 43 (TDP-43) or 3-repeat tau.
• Existing experimental models primarily utilize early genetic mutations, which represent only a fraction of disease cases and pathologies.

Purpose of the Study:

• To highlight the limitations of current experimental models for ALS and FTLD.
• To emphasize the need for newer models that better represent the complex and multigenic nature of these diseases.
• To advocate for a multi-model approach to study diverse aspects of ALS and FTLD.

Main Methods:

• Review of existing literature on ALS and FTLD experimental models.
• Analysis of the molecular pathologies and genetic underpinnings of sporadic and genetic forms of ALS and FTLD.
• Comparison of current models' ability to recapitulate disease aspects.

Main Results:

• Initial genetic models of ALS and FTLD do not fully capture the majority of disease cases or common overlapping pathologies.
• Newer models targeting key molecular pathologies are scarce and may lack critical disease aspects.
• The complexity and multigenic nature of these diseases necessitate diverse experimental approaches.

Conclusions:

• Current experimental models are insufficient for fully understanding ALS and FTLD.
• Developing and utilizing a variety of models targeting different disease aspects is crucial.
• A comprehensive understanding requires integrating data from multiple, relevant experimental models.