Axonal Transport of TDP-43 mRNA Granules Is Impaired by ALS-Causing Mutations

Abstract

Summary The RNA binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is a major component of the cytoplasmic inclusions characteristic of amyotrophic lateral sclerosis and some types of frontotemporal lobar degeneration. The importance of TDP-43 in disease is underscored by the fact that dominant missense mutations are sufficient to cause disease, although the role of TDP-43 in pathogenesis is unknown. Here we show that TDP-43 forms cytoplasmic mRNP granules that undergo bidirectional, microtubule-dependent transport in neurons in vitro and in vivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function in vivo and in vitro, including in stem cell-derived motor neurons from ALS patients bearing any one of three different TDP-43 ALS-causing mutations. Thus, TDP43 mutations that cause ALS lead to partial loss of a novel cytoplasmic function of TDP-43.

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

“…Additionally, several recent reports support the idea that the axonal transcriptome and proteome are changed in amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). For example, ALS-causing mutations in the RNA-binding protein TDP-43 impairs axonal trafficking of mRNA granules to distal axons [41]. Similarly, reduced levels of survival of motor neuron (SMN) decrease axonal mRNA localization and human SMN1 mutations that alter the amount of functional protein are responsible for most SMA cases [42].…”

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

“…Disease-causing mutations in TARDBP reduce the density and mobility of these RNA particles and interfere with their transport into dendrites [20,51]. These results suggest that dysregulation of TDP43 or FUS through inherited mutations or acquired mislocalization might inhibit mRNA transport and localized translation, both of which are essential for proper neuronal function.…”

“…Within the nucleus, TDP43 has essential roles in RNA transcription, splicing, and stability [13,14,[47][48][49][50], and transports select mRNA to localized sites of translation within the cytoplasm [20,51,52]. In addition to its function in RNA trafficking, cytoplasmic TDP43 also helps regulate RNA translation and homeostasis by sequestering transcripts in RNA granules [53][54][55][56].…”

“…In addition to their roles in sequestering RNAs within stress granules, TDP43 and FUS shuttle RNA from the nucleus to the dendrites in an activity-dependent process [20,51,52,104]. Disease-causing mutations in TARDBP reduce the density and mobility of these RNA particles and interfere with their transport into dendrites [20,51].…”

“…Mounting genetic evidence suggests that motor neuron degeneration in ALS represents a final common pathway initiated by ≥1 conserved upstream mechanisms, including protein misfolding/aggregation [5][6][7][8][9][10][11][12], RNA misprocessing [10,[13][14][15][16][17][18][19], and disruptions in axonal transport [12,[20][21][22][23][24]. These mechanisms are not mutually exclusive, and instead may enhance one another, thereby accentuating neurodegeneration in ALS.…”