Alzheimer  >   B. The Pathogenesis of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that affects motor neurons in the motor cortex, brainstem, and spinal cord. These motor neurons control voluntary muscles so that patients have difficulty in walking, speaking or other forms of voluntary movement. Pathologically, ALS is characterized by the inclusion bodies comprising cleaved or abnormally phosphorylated TAR DNA-binding protein 43 (TDP-43). This chapter will discuss how neuronal hyperexcitability may lead to TDP-43 pathology and why motor neurons do not exhibit Tau pathology.

Neuronal Hyperexcitability in ALS

It has been well established that ALS originates from hyperexcitability in the cerebral cortex (Eisen et al., 1993; Vucic et al., 2008; Menon et al., 2015). Expression of mutant SOD1 or TDP-43 in animal models has been shown to cause hyperexcitability of pyramidal neurons in the layer V of motor cortex (Fogarty et al., 2015; Fogarty et al., 2016). These cortical neurons project to the spinal cord, thus known as corticospinal motor neurons which include the giant Betz cells. The corticospinal motor neurons form synaptic connections with lower motor neurons in the brainstem and spinal cord. Hence, the cortical hyperexcitability may lead to excessive stimulation of excitatory glutamatergic synapses, resulting in excitotoxicity in both upper and lower motor neurons. This led to the hypothesis that ALS could be a synaptopathy, arising from excessive glutamatergic synaptic transmission (Fogarty, 2019).

What causes hyperexcitability of corticospinal motor neurons? Several lines of evidence suggest that the cortical hyperexcitability could originate in layer III somatostatin-positive interneurons (SOM cells) and pyramidal neurons (Article 1).

From Hyperexcitability to TDP-43 Pathology

In addition to genetic mutations, phosphorylated or cleaved TDP-43 can also result in the loss of its normal functions. This may originate from hyperexcitability and the consequent Ca2+ overload. TDP-43 can be cleaved by calpain (Yamashita et al., 2012). Its pathological phosphorylation is catalyzed by casein kinase-1 (CK1) (Hasegawa et al., 2008). Calpain is directly activated by high level of Ca2+ ions. CK1 also depends on Ca2+, but indirectly. Ca2+ may stimulate protein phosphatase 2B (PP2B or calcineurin) to dephosphorylate CK1, resulting in its activation (Liu et al., 2002; Nakano et al., 2010).

Normal Functions of TDP-43

TDP-43 promotes the biogenesis of microRNAs from newly transcribed microRNA, i.e., the primary transcript (pri-miRNA). First, pri-miRNA is cleaved by the microprocessor complex consisting of Drosha and DGCR8. This results in a shorter microRNA-precursor denoted by pre-miRNA (Figure B-1). Subsequently, the pre-miRNA is transported from the nucleus to the cytoplasm for further processing by the Dicer complex, which leads to a mature microRNA (Ye et al., 2016).


Figure B-1. The biogenesis of a microRNA. TDP-43 promotes microRNA biogenesis by interacting with the nuclear Drosha complex and the cytoplasmic Dicer complex. The mutant C9ORF72 disrupts microRNA biogenesis by binding to Drosha. [Modified from: Wikipedia]

The loss of normal TDP-43 functions may cause detrimental effects. TDP-43 targets miR-132 and miR-9 (Kawahara and Mieda-Sato, 2012; Freischmidt et al., 2013; Zhang et al., 2013). As discussed in Chapter 11, miR-132 plays a critical role in Alzheimer's disease and other tauopathies by regulating the expression of Tau protein. However, in motor neurons, Tau does not play a significant role in excitability (discussed in the next section).

It has been shown that miR-132 regulates not only the expression of Tau protein, but also TMEM106B (Chen-Plotkin et al., 2012), which is implicated in both FTLD-TDP and ALS (Vass et al., 2011). miR-132 deficiency leads to TMEM106B upregulation, thereby resulting in TDP-43 pathology, possibly through impaired TDP-43 clearance (Nicholson and Rademakers, 2016).

miR-9 targets neurofilaments which are a major component of the neuronal cytoskeleton, located primarily in the axon. Their dysregulation has been shown to play an important role in the pathogenesis of ALS (Collard et al., 1995). In the cerebrospinal fluid (CSF) of ALS patients, levels of neurofilament heavy and light chains are significantly elevated (Xu et al., 2016; Rossi et al., 2018). TDP-43 mutations result in miR-9 down-regulation (Zhang et al., 2013), which may account for neurofilament dysregulation in TDP-43 pathology.

Tau Pathology in ALS

Motor neurons do not exhibit Tau pathology (Arai et al., 2006). According to the model presented in Chapter 9, Tau pathology arises from hyperexcitability induced by elevated total and/or 4R-Tau at the axon initial segments (AIS). In ALS, the hyperexcitability of motor neurons is caused by excessive excitatory synaptic inputs (Fogarty, 2019), rather than excessive Tau expression. Generally speaking, the neurons participating in long-range communication may exhibit Tau pathology because their AIS microtubules could act as receiving antennas. Two lines of evidence suggest that motor neurons are not engaged in long-range communication.

  1. To act as receiving antennas, the microtubule-mediated excitability should be sensitive to the electric fields from transmitting neurons. At AIS, several microtubules are bundled into a fascicle, possibly to enhance the sensitivity of microtubules to electric fields such that a weak field from transmitting neurons is sufficient to change excitability. In the motor neurons of the spinal cord, the number of microtubules per fascicle at AIS ranges from three to five, but in the pyramidal neurons of the cerebral cortex, the number can reach 22 (see Article 2).
  2. Action potentials initiate at AIS due to its lower threshold than at other regions. It was thought that AIS must contain very high density of voltage-gated sodium channels to reduce threshold. In spinal cord motor neurons, the density of sodium channels at AIS is indeed very high, but not in pyramidal neurons of neocortex. Their difference could be explained by the effects of AIS microtubules (see Article 3).

There is a reason why motor neurons should not be engaged in long-range synchronization. Motor neurons control the movement of the body on the left and right sides separately, because in many cases, we would like to move only one hand, not both hands together. The long-range synchronization via electromagnetic (EM) waves may cover the entire brain. Hence, motor neurons cannot be synchronized by EM waves.

In plain ALS, hyperphosphorylated Tau is present in layer II/III of the frontal cortex, not in layer V corticospinal motor neurons or lower motor neurons (Yang et al., 2008). As mentioned above, cortical hyperexcitability in ALS could originate in layer III SOM cells and pyramidal neurons. These neurons are likely to participate in long-range communication. The cognitive function requires long-range communication among widely separated brain areas, even between two cerebral hemispheres. Therefore, in ALS with cognitive impairment, Tau pathology is widespread (Yang and Strong, 2012; Moszczynski et al., 2018).

Related Articles

1. The Origin of Cortical Hyperexcitability in ALS

2. Microtubules at the Axon Initial Segment

3. Why are Action Potentials initiated at AIS?


Author: Frank Lee
First published: August 11, 2019