Lingo-1 expression is increased in essential tremor cerebellum and is present in the basket cell pinceau

Abstract

The Lingo-1 sequence variant has been associated with essential tremor (ET) in several genome wide association studies. However, the role that Lingo-1 might play in pathogenesis of ET is not understood. Since Lingo-1 protein is a negative regulator of axonal regeneration and neurite outgrowth, it could contribute to Purkinje cell (PC) or basket cell axonal pathology observed in postmortem studies of ET brains. In this study, we used Western blotting and immunohistochemistry to examine Lingo-1 protein in ET vs. control brains. In Western blots, Lingo-1 protein expression level was significantly increased in cerebellar cortex (1.56 ± 0.46 in ET cases vs. 0.99 ± 0.20 in controls, p = 0.002), but was similar in the occipital cortex (p = 1.00) of ET cases vs. controls. Lingo-1 immunohistochemistry in cerebellum revealed that Lingo-1 was enriched in the distal axonal processes of basket cells, which formed a “pinceau” structure around the PC axon initial segment (AIS). We found that some Lingo-1 positive pinceau had abnormally elongated processes, targeting PC axon segments distal to the AIS. In ET cases, the percentage of Lingo-1 positive pinceau that were ≥30µm or ≥40 µm in length was increased 2.4- to 4.1-fold, respectively, vs. pinceau seen in control brains (p<0.0001). Elongated Lingo-1 positive pinceau strongly correlated with number of PC axonal torpedoes and a rating of basket cell axonal pathology. The increased cerebellar Lingo-1 expression and elongated Lingo-1 positive pinceau processes could contribute to the abnormal PC and basket cell axonal pathology and cerebellar dysfunction observed in ET.

Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1

“…In this report, we demonstrate that the cerebellar network is altered in SCA1 even earlier than this through the involvement of cerebellar stem cells. These cells, identified just disorder that is cerebellar in origin (31,43,44). This, along with our observation that BC morphology correlates with CAG expansion and disease severity, supports the notion that this structural abnormality is truly pathogenic.…”

Identification of candidate genes for familial early-onset essential tremor

“…55,56 In family D, the gene, brain link 2 (BRAL2; also known as HAPLN4) was identified as a candidate. It is of special interest that BRLA2 is highly expressed throughout the GABA-ergic neurons of the cerebellum, including Purkinje cells and basket neurons, both of which have been shown in some studies to be abnormal in ET 57,58 in postmortem studies of humans with ET. Furthermore, the Purkinje cells, and their entire GABA-ergic output, are directed at the neurons in the deep cerebellar nuclei.…”

Linking Essential Tremor to the Cerebellum: Neuropathological Evidence

“…Additional changes, possibly the result of secondary remodeling, have also been observed in neighboring neuronal populations. These include changes in basket cell axonal processes [i.e., hypertrophy of perisomal processes ("hairy baskets") and elongated leucine-rich repeat and Ig domain containing 1 (LINGO1) labeled pinceau processes] [10,11] and, possibly, changes in the distribution of climbing fiber-Purkinje cell synapses [12]. Finally, regional changes, including a reduction in cerebellar cortical excitatory amino acid transporter type 2 (EAAT2) protein levels in ET, suggest that Purkinje cells in ET might be more vulnerable to excitotoxic damage than those of controls [13] (Table 1).…”