Better understanding the neurobiology of primary lateral sclerosis

Abstract

Primary lateral sclerosis (PLS) is a rare neurodegenerative disease characterized by progressive degeneration of upper motor neurons (UMNs). Recent studies shed new light onto the cellular events that are particularly important for UMN maintenance including intracellular trafficking, mitochondrial energy homeostasis and lipid metabolism. This review summarizes these advances including the role of Alsin as a gene linked to atypical forms of juvenile PLS, and discusses wider aspects of cellular pathology that have been observed in adult forms of PLS. The review further discusses the prospects of new transgenic upper motor neuron reporter mice, human stem cell-derived UMN cultures, cerebral organoids and non-human primates as future model systems to better understand and ultimately treat PLS.

Keywords:

• primary lateral sclerosis
• Betz cell
• upper motor neuron
• corticospinal motor neuron
• Alsin
• ALS2
• endosomes
• mitochondria
• Golgi apparatus
• bioenergetics
• membrane lipids

Acknowledgements

We thank Drs. Giorgia Quadrato (USC, Los Angeles, USA) and Vincenzo Silani (Dept. Neurology, Milan University, Italy) for helpful comments and suggestions, the Second International PLS Conference, Philadelphia, 2019, was supported by the National Institutes of Neurological Disorders and Stroke (NINDS), the Spastic Paraplegia Foundation (SPF), the Motor Neuron Disease Association (MNDA), The ALS Association, Mr. David Marren and his family, Mitsubishi-Tanabe Pharma, and Biogen. The supplement received financial support from Biogen and SPF. We are grateful to the PLS patients who attended the conference and actively participated in the discussions.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

PHO is supported by NIH-NIA [grant RO1AG061708]. GM is funded by NIH [grant R01NS093872] and the ALS Association. CK is funded by the Muscular Disease Association. GH is supported by Agence Nationale pour la Recherche (ANR) in the frame of an eRARE3 call (grant Repetomics), the Association Française contre les Myopathies (AFM) and the Fédération pour la Recherche sur le Cerveau (FRC). The UCSD Light Microscopy Core is funded by NINDS NS047101.