cells Review Much More Than a Scaffold: Cytoskeletal Proteins in Neurological Disorders Diana C. Muñoz-Lasso 1 , Carlos Romá-Mateo 2,3,4, Federico V. Pallardó 2,3,4 and Pilar Gonzalez-Cabo 2,3,4,* 1 Department of Oncogenomics, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; [email protected] 2 Department of Physiology, Faculty of Medicine and Dentistry. University of Valencia-INCLIVA, 46010 Valencia, Spain; [email protected] (C.R.-M.); [email protected] (F.V.P.) 3 CIBER de Enfermedades Raras (CIBERER), 46010 Valencia, Spain 4 Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain * Correspondence: [email protected]; Tel.: +34-963-395-036 Received: 10 December 2019; Accepted: 29 January 2020; Published: 4 February 2020 Abstract: Recent observations related to the structure of the cytoskeleton in neurons and novel cytoskeletal abnormalities involved in the pathophysiology of some neurological diseases are changing our view on the function of the cytoskeletal proteins in the nervous system. These efforts allow a better understanding of the molecular mechanisms underlying neurological diseases and allow us to see beyond our current knowledge for the development of new treatments. The neuronal cytoskeleton can be described as an organelle formed by the three-dimensional lattice of the three main families of filaments: actin filaments, microtubules, and neurofilaments. This organelle organizes well-defined structures within neurons (cell bodies and axons), which allow their proper development and function through life. Here, we will provide an overview of both the basic and novel concepts related to those cytoskeletal proteins, which are emerging as potential targets in the study of the pathophysiological mechanisms underlying neurological disorders. Keywords: actin; tubulin; neurofilaments; microtubules; neuron; growth cone; cytoskeleton; neurological diseases 1. Neuronal Cytoskeleton The cytoskeleton is a cellular organelle formed by a three-dimensional scaffold of proteins that is particularly essential for the definition of the physiological properties of neurons. Since the development of the nervous system and throughout its entire existence, the cytoskeleton is essential to maintain neuronal functions. Neurons are morphologically distinguished from other cells because they have a compartmentalized structure: dendrites, a cell body (or neuronal soma), an axon, and axon terminals. In each compartment, cytoskeletal proteins have specific functions that ensure, as a final goal, the transmission of electrical and chemical signals between neurons. The neuronal cytoskeleton has to be both a flexible and dynamic organelle to maintain the neuronal circuit functioning through the life of an organism. It depends on three classes of filaments: intermediate filaments (IF), which are protein-based neurofilaments (10 nm in diameter), actin-based microfilaments (6 nm in diameter), and tubulin-based microtubules (24 nm in diameter) (Figure1). In addition to these proteins, other filament-binding proteins regulate the organization and dynamics of these components. Cells 2020, 9, 358; doi:10.3390/cells9020358 www.mdpi.com/journal/cells Cells 2020, 9, 358 2 of 41 Cells 2019, 8, x 2 of 43 Figure 1. Main elements of the neuronal cytoskeleton. The neuronal cytoskeleton is mainly Figure 1. Main elements of the neuronal cytoskeleton. The neuronal cytoskeleton is mainly composed composed of neurofilaments, actin filaments, and microtubules. In neurons, actin filaments and of neurofilaments, actin filaments, and microtubules. In neurons, actin filaments and microtubules are microtubules are very dynamic in response to physiological needs, for example, during the very dynamic in response to physiological needs, for example, during the embryonic development of embryonic development of the nervous system and the axonal regeneration of peripheral nerves the nervous system and the axonal regeneration of peripheral nerves after damage. Here, neurons after damage. Here, neurons need to grow a new axon and direct it to their right target. For this need to grow a new axon and direct it to their right target. For this particular task, neurons use the particulargrowth cone,task, aneurons motile structureuse the growth rich in actin cone, and a moti microtubulesle structure as wellrich asin otheractin cytoskeletaland microtubules components. as wellScale as other bar 10 cytoskeletalµm. components. Scale bar 10 μm. In Inneurons, neurons, neurofilaments neurofilaments are are the the structural structural core core of ofmyelinated myelinated axons axons and and modulate modulate the the axonalaxonal diameter diameter [1–3], [1–3 which], which is essential is essential for for mainta maintainingining axonal axonal transport transport [4] [ 4and] and nerve nerve conduction conduction velocityvelocity [5,6]. [5,6 In]. Inmature mature axons, axons, microfilaments microfilaments form form both both stable stable structures, structures, such such as asactin actin rings, rings, and and dynamicdynamic structures, structures, such such as ashotspo hotspotsts and and trails. trails. In Indeveloping developing or orregenerating regenerating axons axons of ofall allneurons, neurons, microfilamentsmicrofilaments form form dynamic dynamic structures, structures, such asas thethe lamellipodia lamellipodia and and filopodia, filopodia, in thein the growth growth cones cones(GCs). (GCs). On theOn otherthe other side, side, microtubules microtubules overlap over tolap provide to provide neurons neurons with with continuous continuous transport transport tracks tracksthat that allow allow active active mitochondrial mitochondrial [7,8], [7,8], vesicular vesicular [9,10 [9,10],], and and mRNA mRNA [11,12 [11,12]] transport transport along along the axonsthe axonsand and in the in growththe growth cone, cone, thus thus ensuring ensuring neuronal neuronal homeostasis. homeostasis. TheseThese three three elements elements (neurofilaments, (neurofilaments, microfil microfilaments,aments, and and microtubules) microtubules) work work together together to to guaranteeguarantee a aproper proper formation formation of thethe nervousnervous system system during during the the embryonic embryonic development development and and to assure to assureits function its function in adulthood. in adulthood. There There are three are three particular particular events events where where the function the function of cytoskeletal of cytoskeletal proteins proteinsis required: is required: first, during first, embryonicduring embryonic development, development, where the where cytoskeleton the cytoskeleton participates participates in the growth in theand growth guidance and ofguidance axons (for of aaxons review (for see, a [review13,14]); second,see, [13,14]); during second, adult life,during where adult neurons life, where depend neuronson the depend cytoskeleton on the for cytoskeleton maintaining for neuronal maintainin homeostasisg neuronal and homeostasis neuronal plasticity and neuronal [15–18 ];plasticity and third, [15–18];when theand peripheral third, when axon the needs peripheral to regenerate axon afterneeds being to regenerate injured. In after this lastbeing event, injured. peripheral In this neurons last event, peripheral neurons (for a review, see [19]) require a specific set of cytoskeletal proteins to ensure nerve regeneration upon damage [20,21]. Given the importance of cytoskeleton for neurons, it is not surprising that several neurological disorders either involve changes in the expression, dynamics, and stability of cytoskeletal proteins Cells 2020, 9, 358 3 of 41 (for a review, see [19]) require a specific set of cytoskeletal proteins to ensure nerve regeneration upon damage [20,21]. Given the importance of cytoskeleton for neurons, it is not surprising that several neurological disorders either involve changes in the expression, dynamics, and stability of cytoskeletal proteins or are the result of their mutations. In this review, we will study the basic knowledge of the structure and function of cytoskeletal proteins in neurons, and highlight discoveries that may be relevant to understand the molecular mechanisms underlying some neurological disorders. 1.1. Intermediate Filaments Intermediate filaments (IFs) are the major cytoskeletal proteins in neurons. In contrast to microfilaments and microtubules, IFs are more heterogeneous, have tensile strength, do not have polarity, and do not participate in cell motility. There are seven classes of IFs-proteins (Table1) and among these, three classes have a distinctive function in cells of the nervous system (neurons and glial cells): Type III (Desmin, DES; the Glial Fibrillary Acidic Protein, GFAP; Peripherin, PRPH and Vimentin, VIM); Type IV (α-Internexin, INA; Neurofilament light, NF-L; Neurofilament medium, NF-M; Neurofilament heavy, NF-H and Syncoilin, SYNC); and Type VI (Nestin, NES and Synemin, SYNM). Table 1. Classification of intermediate filaments. Intermediate Filament Protein Name Gene Name Uniprot ID Type I and II Acidic and basic keratins 44 genes Desmin DES P17661 Type III Glial fibrillary acidic protein GFAP P14136 Peripherin PRPH P41219 Vimentin VIM P08670 Internexin neuronal intermediate filament INA Q16352 protein, alpha Neurofilament light polypeptide NEFL P07196 Type IV Neurofilament medium polypeptide NEFM P07197 (neurofilament 3) Neurofilament heavy polypeptide NEFH P12036 Syncoilin 1 SYNC Q9H7C4 Lamin A/C LMNA P02545 Type V LMNB1 P20700 Lamin B LMNB2 Q03252 Nestin NES P48681 Type VI Synemin SYNM O15061