Propagation of TDP-43 proteinopathy in neurodegenerative disorders

Abstract

Neurodegenerative disorders are characterized by disruptions to neuronal function and circuitry, leading to a variety of clinical syndromes depending on the affected neuroanatomic regions (Geula, 1998). Many proteinopathies implicated in neurodegenerative diseases are characterized by the pathologic accumulation of proteins into inclusions that are initially deposited in specific areas of the brain and spread widely with disease progression, leading to significant neuronal loss and gliosis (Brettschneider et al., 2013, 2014; Josephs et al., 2016; Jamshidi et al., 2020). There is substantial evidence that amyloid-β, phosphorylated tau, and α-synuclein spread through cell-to-cell propagation of pathological seeds in a prion-like manner, most likely involving trans-synaptic spread of pathology (Brettschneider et al., 2013). In recent years, research has begun to address the mechanism of propagation underlying the transactive response DNA-binding protein 43-kDa (TDP-43) abnormal species of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) (Brettschneider et al., 2013). In a recent study, our laboratory produced evidence suggesting that TDP-43 inclusions spread throughout the hippocampus in a manner that supports transsynaptic propagation along axonal pathways (Jamshidi et al., 2020). Here, we briefly review prior research on the propagation of TDP-43 pathology and suggest putative mechanisms. TDP-43 in neurodegenerative disorders: TDP-43 is an RNA/DNA-binding protein that is located primarily within the nucleus in non-pathological states and is an essential part of messenger ribonucleoprotein particles involved in RNA processing (Wong et al., 2021). In contrast, pathological TDP-43 is largely phosphorylated and mislocalized in the cytoplasm and processes of neurons where its clearance is disrupted, and accumulation of TDP-43 in the cytoplasm, nuclei, and neurites contributes to neurodegeneration (Ding et al., 2015; Iguchi et al., 2016; Wong et al., 2021). TDP-43 inclusions are commonly found at autopsy in a large proportion of the brains of individuals diagnosed with frontotemporal lobar degeneration (FTLD-TDP), which accounts for a substantial share of dementia diagnoses under age 65 (Brettschneider et al., 2014). Although five subtypes of TDP-43 inclusions have been described (types A-E), types A, B, and C account for the majority of FTLD-TDP cases (Mackenzie et al., 2011). Briefly, TDP-43 type A is characterized by the presence of neuronal cytoplasmic inclusions, neuronal intranuclear inclusions, and short dystrophic neurites; type B by the predominance of cortical neuronal cytoplasmic inclusions; and type C by the predominance of long, thick cortical dystrophic neurites (Mackenzie et al., 2011). Clinical syndromes associated with TDP-43 proteinopathy: FTLD-TDP may present as a variety of clinical dementia syndromes, including behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), and ALS (Mackenzie et al., 2011). Patients with bvFTD typically demonstrate changes in personality and comportment with or without executive functioning deficits (Rascovsky et al., 2011). In contrast, PPA is characterized by a salient progression in language dysfunction, with primary deficits in grammaticality (agrammatic PPA), word retrieval (logopenic PPA), and single-word comprehension (semantic PPA) (Mesulam et al., 2014). In ALS, pathologic accumulation and spread of TDP-43 inclusions in the brain and spinal cord contributes to a significant loss of motor neurons, ultimately leading to paralysis and death, with a subset of patients also showing deficits characteristic of bvFTD (Brettschneider et al., 2013, 2014). TDP-43 types A and B are implicated in bvFTD and ALS, whereas type B is frequently found in agrammatic PPA, and type C is the most common cause of semantic PPA (Mackenzie et al., 2011). TDP-43 precipitates that are considered “non-FTLD” can also accumulate in medial temporal areas, often in the presence of comorbid hippocampal sclerosis and/or Alzheimer's disease pathology, and contribute to an amnestic phenotype (Josephs et al., 2016). Stages of TDP-43 proteinopathy progression: Over the past decade, researchers have characterized the stages by which TDP-43 inclusions spread throughout the brain, varying according to the specific clinical dementia syndrome or the presence of multiple co-occurring pathologies (Josephs et al., 2016). For example, in bvFTD due to TDP-43 type A or B, TDP-43 deposition begins in the amygdala, orbital gyri, and gyrus rectus (stage I); spreads to the middle frontal gyrus, anterior cingulate gyrus, anteromedial temporal lobe regions, superior and medial temporal gyri, striatum, red nucleus, thalamus, and precerebellar nuclei (stage II); progresses to the motor cortex, bulbar somatomotor neurons, and the spinal cord anterior horn (stage III); and finally reaches the visual cortex (stage IV) (Brettschneider et al., 2014). This hier