Understanding ALS: the central role of the endoplasmic reticulum (ER) and mitochondria1,2

Over the past decade, understanding of the multiple destructive pathways that lead to neuronal death in amyotrophic lateral sclerosis (ALS) has greatly improved.3,4

The ER and mitochondria play a critical role in maintaining neuronal health and survival, and function as a convergence point for many destructive pathways in ALS.1,2,5,6

The pathophysiological mechanisms underlying ALS are multifactorial, with evidence of a complex interaction between genetic changes and molecular pathways feeding into downstream pathways that result in neuronal death.7-9

Properly modulated and functioning pathways in the ER and mitochondria are critical for keeping neurons alive and functioning. Dysfunctional, ALS-related disease pathways can lead to ER stress, mitochondrial dysfunction, and, ultimately, neuronal death.1,2,6

Deepening knowledge has revealed the importance and interconnectedness of the ER and mitochondria in maintaining neuronal health and survival; dysfunction in one can be transmitted to the other through specialized interactions between the 2.1,2,5,6

Mitochondrial dysfunction and release of cytochrome C, along with an imbalance of pro- and antiapoptotic factor production, trigger the mitochondrial apoptotic pathway, leading directly to neuronal death.2

ER stress and dysfunction, in combination with abnormal DNA transcription, lead to misfolded proteins and accumulating protein aggregates.3,7,9

ER stress and mitochondrial dysfunction can also lead to altered communication between these 2 closely linked organelles, accelerating the feedback loop and eventually initiating a cellular sequence ending in neuronal death.1,2,6,10

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Due to the many mechanisms underlying ALS, targeting multiple pathways, including those central to neuronal death through the ER and mitochondria, will likely be necessary to effectively impact the course of the disease.1,2,4,7-9,11

The ALSFRS-R: refresh what you know about this primary functional end point in clinical trials for ALS

The ALS Functional Rating Scale-Revised (ALSFRS-R) is the most widely accepted outcome measure of activity limitation for patients with ALS. It comprises 12 items rated on a scale of 0 to 4 (4 = normal function; 0 = complete loss of function). The 12 items are grouped into 4 domains: bulbar, fine motor, gross motor, and respiratory.12,13

Each point decrease on the ALSFRS-R represents lost capability in performing activities fundamental to daily life.

  • Bulbar13
  • Example score

    Swallowing (bulbar function)

    A score of 4:
    Patient has normal eating habits.

    A score of 3:
    Patient experiences first stages of eating problems and occasional choking.

    A score of 2:
    Swallowing has become increasingly difficult and changes to food consistency are necessary.

    1. Normal speech processes
    2. Detectable speech disturbance
    3. Intelligible with repeating
    4. Speech combined with nonvocal communication
    5. Loss of useful speech
    1. Normal
    2. Slight but definite excess of saliva in mouth; may have nighttime drooling
    3. Moderately excessive saliva; may have minimal drooling
    4. Marked excess of saliva with some drooling
    5. Marked drooling; requires constant tissue or handkerchief
    1. Normal eating habits
    2. Early eating problems—occasional choking
    3. Dietary consistency changes
    4. Needs supplemental tube feeding
    5. NPO (exclusively parenteral or enteral feeding)
  • Fine Motor13
  • Gross Motor13
  • Respiratory13

Even the loss of a single point can reflect severe limitations on a patient’s independence. See how by reading Robert’s story.

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References: 1. Manfredi G, Kawamata H. Mitochondria and endoplasmic reticulum crosstalk in amyotrophic lateral sclerosis. Neurobiol Dis. 2016;90:35-42. doi:10.1016/j.nbd.2015.08.004. 2. Smith EF, Shaw PJ, De Vos KJ. The role of mitochondria in amyotrophic lateral sclerosis. Neurosci Lett. 2019;710:132933. doi:10.1016/ j.neulet.2017.06.052. 3. Hardiman O. Major advances in amyotrophic lateral sclerosis in 2020. Lancet Neurol. 2021;20(1):14-15. doi:10.1016/S1474-4422(20)30447-6. 4. Kiernan MC, Vucic S, Talbot K, et al. Improving clinical trial outcomes in amyotrophic lateral sclerosis. Nat Rev Neurol. 2021;17(2):104-118. doi:10.1038/s41582-020-00434-z. 5. Paillusson S, Stoica R, Gomez-Suaga P, et al. There’s something wrong with my MAM; the ER–mitochondria axis and neurodegenerative diseases. Trends Neurosci. 2016;39(3):146-157. doi:10.1016/j.tins.2016.01.008. 6. Bernard-Marissal N, Chrast R, Schneider BL. Endoplasmic reticulum and mitochondria in diseases of motor and sensory neurons: a broken relationship? Cell Death Dis. 2018;9(3):333. doi:10.1038/s41419-017-0125-1. 7. Hardiman O, Al-Chalabi A, Chio A, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 2017;3:17071. doi:10.1038/nrdp.2017.71. 8. Brown RH, Al-Chalabi A. Amyotrophic lateral sclerosis. N Engl J Med. 2017;377(2):162-172. doi:10.1056/NEJMra1603471. 9. Ghasemi M, Brown RH Jr. Genetics of amyotrophic lateral sclerosis. Cold Spring Harb Perspect Med. 2018;8(5):a024125. doi:10.1101/cshperspect.a024125. 10. Sathasivam S, Shaw PJ. Apoptosis in amyotrophic lateral sclerosis: what is the evidence? Lancet Neurol. 2005;4(8):500-509. doi:10.1016/S1474-4422(05)70142-3. 11. Muyderman H, Chen T. Mitochondrial dysfunction in amyotrophic lateral sclerosis: a valid pharmacological target? Br J Pharmacol. 2014;171(8):2191-2205. doi:10.1111/bph.12476. 12. Paganoni S, Macklin EA, Lee A, et al. Diagnostic timelines and delays in diagnosing amyotrophic lateral sclerosis (ALS). Amytroph Lateral Scler Frontotemporal Degener. 2014;15(5-6):453-456. doi:10.3109/21678421.2014.903974. 13. Cedarbaum JM, Stambler N, Malta E, et al; BDNF ALS Study Group (Phase III). The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. J Neurol Sci. 1999;169(1-2):13-21. doi:10.1016/S0022-510X(99)00210-5.

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