The Selective Loss of Purkinje Cells Induces Specific Peripheral Immune Alterations

Abstract

The progression of neurodegenerative diseases is reciprocally associated with impairments in peripheral immune responses. We investigated different contexts of selective neurodegeneration to identify specific alterations of peripheral immune cells and, at the same time, discover potential biomarkers associated to this pathological condition. Consequently, a model of human cerebellar degeneration and ataxia -the Purkinje Cell Degeneration (PCD) mouse- has been employed, as it allows the study of different processes of selective neuronal death in the same animal, i.e., Purkinje cells in the cerebellum and mitral cells in the olfactory bulb. Infiltrated leukocytes were studied in both brain areas and compared with those from other standardized neuroinflammatory models obtained by administering either gamma radiation or lipopolysaccharide. Moreover, both myeloid and lymphoid splenic populations were analyzed by flow cytometry, focusing on markers of functional maturity and antigen presentation. The severity and type of neural damage and inflammation affected immune cell infiltration. Leukocytes were more numerous in the cerebellum of PCD mice, being located predominantly within those cerebellar layers mostly affected by neurodegeneration, in a completely different manner than the typical models of induced neuroinflammation. Furthermore, the milder degeneration of the olfactory bulb did not foster leukocyte attraction. Concerning the splenic analysis, in PCD mice we found: (1) a decreased percentage of several myeloid cell subsets, and (2) a reduced mean fluorescence intensity in those myeloid markers related to both antigen presentation and functional maturity. In conclusion, the selective degeneration of Purkinje cells triggers a specific effect on peripheral immune cells, fostering both attraction and functional changes. This fact endorses the employment of peripheral immune cell populations as concrete biomarkers for monitoring different neuronal death processes.

Intracerebellar injection of monocytic immature myeloid cells prevents the adverse effects caused by stereotactic surgery in a model of cerebellar neurodegeneration

“…As IMCs can modulate neuroinflammation after neural damage [ 9 ], we analyzed the different microglial populations of the three experimental groups of PCD mice. The analysis was focused on the molecular and Purkinje cell layers, as these are the layers most affected by the pcd mutation [ 38 ]. Two-way ANOVA tests revealed significant differences for both reactive and anti-inflammatory microglia (Fig.…”

“…Here it is necessary to note that some infiltrated peripheral leukocytes may be misinterpreted as Iba1 + microglial cells. These cells display a round or rod-shaped morphology, also being negatives for other microglial markers, such as TMEM119, and they have been previously typified in our mouse model [ 38 ]. Such cells were not considered in our study, only including the branched or amoeboid Iba1 + elements that correspond to pure microglial cells.…”

“…Along with this selective neurodegeneration, an exacerbated reactive gliosis occurs in this region, mainly characterized by hypertrophied microglial cell bodies and the apoptosis of oligodendrocytes [ 37 ]. Furthermore, specific alterations in the peripheral immune system have been described [ 38 ].…”

Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease

“…This finding is very interesting because Purkinje cells play a central role in cerebellar development and all cerebellar circuits. Because FINCA disease is a neuroimmunological disease, one hypothesis could be based on the link between progressive neurodegeneration and impaired peripheral immune responses, as exemplified by a recent study demonstrating that the selective loss of Purkinje cells induces specific peripheral immune alterations by attracting leukocytes toward and into the cerebellum of a Purkinje cell degeneration mouse model ( del Pilar et al, 2021 ). In their study, del Pilar et al (2021) also suggested that this phenomenon could serve as an early biomarker of cerebellar degeneration and be responsible for an increased susceptibility to infections.…”

“…Because FINCA disease is a neuroimmunological disease, one hypothesis could be based on the link between progressive neurodegeneration and impaired peripheral immune responses, as exemplified by a recent study demonstrating that the selective loss of Purkinje cells induces specific peripheral immune alterations by attracting leukocytes toward and into the cerebellum of a Purkinje cell degeneration mouse model ( del Pilar et al, 2021 ). In their study, del Pilar et al (2021) also suggested that this phenomenon could serve as an early biomarker of cerebellar degeneration and be responsible for an increased susceptibility to infections. Furthermore, the authors referred to several previous studies that have shown that the progression of neurodegenerative diseases has been reciprocally associated with impairments in peripheral immune responses and responsible for an increased susceptibility to infections, as exemplified by multiple sclerosis, AD, Huntington’s disease, Parkinson’s disease and amyotrophic lateral sclerosis ( Scherzer et al, 2007 ; Björkqvist et al, 2008 ; Ciaramella et al, 2016 ; Fakhoury, 2016 ; Liu and Wang, 2017 ), and the identification of increased amounts of proinflammatory cytokines in cerebrospinal fluid and blood of patients with Alzheimer’s and Parkinson’s ( Boyko et al, 2017 ; Chen et al, 2018 ).…”