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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by upper and lower motor neuron signs. There are, however, cases where upper motor neurons (UMNs) are predominantly affected, leading to clinical presentations of UMN‐dominant ALS or primary lateral sclerosis. Furthermore, cases exhibiting an UMN‐predominant pattern of motor neuron disease (MND) presenting with corticobasal syndrome (CBS) have been sparsely reported. This study aims to clarify the clinicopathological features of patients with UMN‐predominant MND. We reviewed 24 patients with UMN‐predominant MND with TDP‐43 pathology in the presence or absence of frontotemporal lobar degeneration. Additionally, we reviewed the medical records of patients with pathologically‐confirmed corticobasal degeneration (CBD) who received a final clinical diagnosis of CBS (n = 10) and patients with pathologically‐confirmed progressive supranuclear palsy (PSP) who received a final clinical diagnosis of PSP syndrome (n = 10). Of 24 UMN‐predominant MND patients, 20 had a clinical diagnosis of an atypical parkinsonian disorder, including CBS (n = 11) and PSP syndrome (n = 8). Only two patients had antemortem diagnoses of motor neuron disease. UMN‐predominant MND patients with CBS less frequently exhibited apraxia than those with CBD, and they were less likely to meet clinical criteria for possible or probable CBS. Similarly, UMN‐predominant MND patients with PSP syndrome less often met clinical criteria for probable PSP than PSP patients with PSP syndrome. Our findings suggest that UMN‐predominant MND can mimic atypical parkinsonism, and should be considered in the differential diagnosis of CBS and PSP syndrome, in particular when criteria are not met. Heatmap and hierarchical clustering based on neuronal loss in 24 UMN‐predominant MND cases. Two distinct clusters are identified by hierarchical clustering based on neuronal loss. The heatmap reflects the severity of neuronal loss, and a color scale is given at the right. Missing data are shown in gray. Patients are represented with columns, and the study ID of each patient is provided. The main clinical features and diagnoses of each case are shown.

Our understanding of how osteocytes, the principal mechanosensors within bone, sense and perceive force remains unclear. Previous work identified “tethering elements” (TEs) spanning the pericellular space of osteocytes and transmitting mechanical information into biochemical signals. While we identified the heparan sulfate proteoglycan perlecan (PLN) as a component of these TEs, PLN must attach to the cell surface to induce biochemical responses. As voltage-sensitive calcium channels (VSCCs) are critical for bone mechanotransduction, we hypothesized that PLN binds the extracellular α2δ1 subunit of VSCCs to couple the bone matrix to the osteocyte membrane. Here, we showed co-localization of PLN and α2δ1 along osteocyte dendritic processes. Additionally, we quantified the molecular interactions between α2δ1 and PLN domains and demonstrated for the first time that α2δ1 strongly associates with PLN via its domain III. Furthermore, α2δ1 is the binding site for the commonly used pain drug, gabapentin (GBP), which is associated with adverse skeletal effects when used chronically. We found that GBP disrupts PLN::α2δ1 binding in vitro, and GBP treatment in vivo results in impaired bone mechanosensation. Our work identified a novel mechanosensory complex within osteocytes composed of PLN and α2δ1, necessary for bone force transmission and sensitive to the drug GBP.

Our understanding of how osteocytes, the principal mechanosensors within bone, sense and perceive force remains unclear. Previous work identified “tethering elements” (TEs) spanning the pericellular space of osteocytes and transmitting mechanical information into biochemical signals. While we identified the heparan sulfate proteoglycan perlecan (PLN) as a component of these TEs, PLN must attach to the cell surface to induce biochemical responses. As voltage-sensitive calcium channels (VSCCs) are critical for bone mechanotransduction, we hypothesized that PLN binds the extracellular α[sub.2] δ[sub.1] subunit of VSCCs to couple the bone matrix to the osteocyte membrane. Here, we showed co-localization of PLN and α[sub.2] δ[sub.1] along osteocyte dendritic processes. Additionally, we quantified the molecular interactions between α[sub.2] δ[sub.1] and PLN domains and demonstrated for the first time that α[sub.2] δ[sub.1] strongly associates with PLN via its domain III. Furthermore, α[sub.2] δ[sub.1] is the binding site for the commonly used pain drug, gabapentin (GBP), which is associated with adverse skeletal effects when used chronically. We found that GBP disrupts PLN::α[sub.2] δ[sub.1] binding in vitro, and GBP treatment in vivo results in impaired bone mechanosensation. Our work identified a novel mechanosensory complex within osteocytes composed of PLN and α[sub.2] δ[sub.1] , necessary for bone force transmission and sensitive to the drug GBP.

Our understanding of how osteocytes, the principal mechanosensors within bone, sense and perceive force remains unclear. Previous work identified \"tethering elements\" (TEs) spanning the pericellular space of osteocytes and transmitting mechanical information into biochemical signals. While we identified the heparan sulfate proteoglycan perlecan (PLN) as a component of these TEs, PLN must attach to the cell surface to induce biochemical responses. As voltage-sensitive calcium channels (VSCCs) are critical for bone mechanotransduction, we hypothesized that PLN binds the extracellular α δ subunit of VSCCs to couple the bone matrix to the osteocyte membrane. Here, we showed co-localization of PLN and α δ along osteocyte dendritic processes. Additionally, we quantified the molecular interactions between α δ and PLN domains and demonstrated for the first time that α δ strongly associates with PLN via its domain III. Furthermore, α δ is the binding site for the commonly used pain drug, gabapentin (GBP), which is associated with adverse skeletal effects when used chronically. We found that GBP disrupts PLN::α δ binding in vitro, and GBP treatment in vivo results in impaired bone mechanosensation. Our work identified a novel mechanosensory complex within osteocytes composed of PLN and α δ , necessary for bone force transmission and sensitive to the drug GBP.

Our understanding of how osteocytes, the principal mechanosensors within bone, sense and perceive force remains unclear. Previous work identified “tethering elements” (TEs) spanning the pericellular space of osteocytes and transmitting mechanical information into biochemical signals. While we identified the heparan sulfate proteoglycan perlecan (PLN) as a component of these TEs, PLN must attach to the cell surface to induce biochemical responses. As voltage-sensitive calcium channels (VSCCs) are critical for bone mechanotransduction, we hypothesized that PLN binds the extracellular α2δ1 subunit of VSCCs to couple the bone matrix to the osteocyte membrane. Here, we showed co-localization of PLN and α2δ1 along osteocyte dendritic processes. Additionally, we quantified the molecular interactions between α2δ1 and PLN domains and demonstrated for the first time that α2δ1 strongly associates with PLN via its domain III. Furthermore, α2δ1 is the binding site for the commonly used pain drug, gabapentin (GBP), which is associated with adverse skeletal effects when used chronically. We found that GBP disrupts PLN::α2δ1 binding in vitro, and GBP treatment in vivo results in impaired bone mechanosensation. Our work identified a novel mechanosensory complex within osteocytes composed of PLN and α2δ1, necessary for bone force transmission and sensitive to the drug GBP. This work provides insights into the mechanisms underlying mechanotransduction and will inform future studies to understand the mechanisms responsible for the negative effects of GBP on bone.